Intermediates for cephalosporins with sulfur-containing oxyimino side chain

ABSTRACT

Antibacterial compounds of the formula ##STR1## wherein R is a mononuclear carbocyclic aromatic group, a 5-membered aromatic heterocyclic group which contains as the hetero (non-carbon) ring member(s) an oxygen or sulphur atom or an imino or lower alkylimino group and, optionally, one or two nitrogen atoms, or a 6-membered aromatic heterocyclic group which contains one to three nitrogen atoms as the hetero ring member(s); R 1  is hydrogen or a 3-substituent which is usable in cephalosporin chemistry; A is lower alkylene or C 3-7  -cycloalkylene which is optionally substituted with carboxy, carbamoyl, lower alkylcarbamoyl or di(lower alkyl)carbamoyl; Q is lower alkylene or C 3-7  -cycloalkylene which is optionally substituted with carboxy, carbamoyl, lower alkylcarbamoyl or di(lower alkyl)carbamoyl, or the group --NR 2  -- or --NR 2  NR 3  --; R 2  and R 3  are independently hydrogen or lower alkyl; p and m are the zero or 1, n is zero, 1 or 2; R 4  is hydrogen, lower alkanoyl or tri(lower alkyl)silyl; two R 4  groups together represent diphenylmethylene; R 5  is hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, --OCOR 7 , --OCOOR 71 , --N(R 7 ) 2 , --NHCOR 7 , --NHCOOR 71 , --COR 7 , --SR 7 , --SOR 7 , --SO 2  R 7 , --SO 3  H, --COOR 7  or --CON(R 7 ) 2  ; R 6  is hydrogen, lower alkyl or halogen, R 7  is hydrogen or lower alkyl; R 71  is lower alkyl, and the two --OR 4  groups are attached to the phenyl ring via adjacent carbon atoms, 
     as well as readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds and hydrates of compounds of formula I and of their esters and salts.

This is a division of application Ser. No. 07/574,329, filed Aug. 28,1990, now U.S. Pat. No. 5,073,550 which is a division of applicationSer. No. 07/229,960, filed Aug. 9, 1988, now U.S. Pat. No. 5,036,064.

DESCRIPTION OF THE INVENTION

The present invention is concerned with acyl derivatives, and morespecifically antibacterial agents of the formula ##STR2## in which R isa mononuclear, carbocyclic aromatic group, a 5-membered, aromaticheterocyclic group which contains as the hetero (non-carbon) ringmember(s) an oxygen or sulphur atom or an imino or lower alkyliminogroup and, optionally, one or two nitrogen atoms, or a 6-memberedaromatic heterocyclic group which contains one to three nitrogen atomsas the hetero ring member(s); R¹ is hydrogen or a 3-substituent which isusable in cephalosporin chemistry; A is lower alkylene or C₃₋₇-cycloalkylene which is optionally substituted with carboxy, carbamoyl,lower alkylcarbamoyl or di(lower alkyl)carbamoyl; Q is lower alkylene orC₃₋₇ -cycloalkylene which is optionally substituted with carboxy,carbamoyl, lower alkylcarbamoyl or di(lower alkyl)carbamoyl, or thegroup --NR² -- or --NR² NR³ --; R² and R³ are independently hydrogen orlower alkyl; p and m are zero or 1; n is zero, 1 or 2; R⁴ is hydrogen,lower alkanoyl or tri(lower alkyl)silyl, or two of R⁴ together representdiphenylmethylene; R⁵ is hydrogen, lower alkyl, hydroxy, lower alkoxy,halogen, nitro, --OCOR⁷, --OCOOR⁷¹, --N(R⁷)₂, --NHCOR⁷, --NHCOOR⁷¹,--COR⁷, --SR⁷, --SOR⁷, --SO₂ R⁷, --SO₃ H, --COOR⁷ or --CON(R⁷)₂ ; R⁶ ishydrogen, lower alkyl or halogen; R⁷ is hydrogen or lower alkyl; and R⁷¹is lower alkyl, and the two groups --OR⁴ groups are attached to thephenyl ring via adjacent carbon atoms,

as well as with readily hydrolyzable esters and pharmaceuticallyacceptable salts of these compounds and hydrates of compounds of formulaI and of their esters and salts.

The compounds of formula I are present preferably in the syn-isomericform. However, they can also be present as mixtures with thecorresponding anti-isomeric form in which the syn-isomeric formpredominates.

In addition to the above compounds, this invention also encompassespharmaceutical compositions containing such compounds as therapeuticallyactive ingredients and the use of such compounds in the treatment ofbacterial infections.

The term "lower" means having a maximum of 7, preferably a maximum of 4,carbon atoms. The term "alkyl" denotes straight-chain or branchedsaturated hydrocarbon residues such as methyl, ethyl, propyl, isopropyland t-butyl. The term "alkylene" denotes corresponding hydrocarbonresidues having two free valencies such as methylene, dimethylene,ethylidene, propylidene, butylidene, isopropylidene and 1,2-isobutylene.The term "alkoxy" denotes alkyl groups attached via an oxygen atom, suchas methoxy and ethoxy. The term "alkanoyl" denotes residues derived fromstraight-chain or branched, saturated fatty acids such as formyl andacetyl. The term "C₃₋₇ -cycloalkyl" denotes saturated, cyclichydrocarbon residues, i.e., cycloalkyl residues which are optionallysubstituted with alkyl groups such as cyclopropyl, cyclobutyl,cyclohexyl and methylcyclopropyl. The term "C₃₋₇ -cycloalkylene" denotescyclic hydrocarbon residues having two free valencies, such ascyclopropylidene, cyclobutylidene, cyclohexylidene and2-methylcyclopropylidene.

The term "halogen" denotes all four forms: chlorine, fluorine, bromineand iodine, with chlorine being preferred.

The term "mononuclear, carbocyclic aromatic group" refers tounsubstituted or substituted phenyl groups, preferably phenyl groupswhich are optionally mono-, di- or trisubstituted with halogen, hydroxy,nitro, amino, cyano, trifluoromethyl, lower alkyl or lower alkoxy.

The 5-membered, aromatic heterocyclic groups are preferablyunsubstituted or substituted with halogen, hydroxy, nitro, amino, cyano,trifluoromethyl, lower alkoxy or lower alkoxy. They are preferablysubstituted with an amino group. Examples of such heterocycles, whichcan be unsubstituted or substituted, include the following: furyl,thienyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl andtriazolyl. Preferred heterocyclic groups are: 2-amino-4-thiazolyl,5-amino-1,2,4-thiadiazolyl, 2-amino-4-oxazolyl and 2-amino-4-imidazolyl.

The 6-membered, aromatic heterocyclic groups are preferablyunsubstituted or substituted with halogen, hydroxy, nitro, amino, cyano,trifluoromethyl, lower alkyl or lower alkoxy. Examples of suchheterocycle, which can be substituted or unsubstituted, include:pyridyl, pyrimidinyl and triazinyl. The 2-amino-6-pyridyl group is anespecially preferred 6-membered heterocyclic group.

The term "3-substituent which is usable in cephalosporin chemistry"denotes the usual substituents which are present in the 3-position ofthe cephalosporin skeleton of therapeutically active cephalosporins.This term preferably denotes lower alkyl such as methyl, lower alkoxysuch as methoxy, halogen such as chlorine, or the group --CH₂ R' or--CH₂ S--R" in which R' means azido, lower alkanoyloxy, carbamoyloxy,N-(lower alkyl)carbamoyloxy, N,N-di-(lower alkyl)carbamoyloxy or aN-containing heterocyclic group attached via a nitrogen atom and R"means a heterocyclic group attached via a carbon atom.

The term "N-containing heterocyclic group" preferably denotes saturated,partially unsaturated and aromatic heterocyclic groups containing up to4 nitrogen atoms as the hetero atom(s). They are preferably 5- or6-membered and can be fused by a 5- or 6-membered cycloalkane ring or bya benzene ring, and preferably unsubstituted or substituted with loweralkyl or carbamoyl. The nitrogen atom by which the N-containingheterocyclic group is attached can also be quaternary substituted.5-Methyl-2-tetrazolyl and pyridinium-1-yl are examples of N-containingheterocyclic groups.

The term "heterocyclic group" preferably means monocyclic, especially 5-and 6-membered, partially unsaturated or aromatic heterocyclic groupswhich preferably contain as the hetero atom(s) an oxygen or sulphur atomand/or 1-4 nitrogen atoms, as well as bicyclic, especially 8-10membered, partially unsaturated or aromatic heterocyclic groups whichpreferably contain as the hetero atom(s) an oxygen or sulphur atomand/or 1-5 nitrogen atoms. These groups are preferably unsubstituted ormono-, di- or tri-substituted with lower alkyl, lower alkoxy, loweralkanediyl, halogen, trifluoromethyl, hydroxy, oxo, carboxy, loweralkoxycarbonyl, carbamoyl, N-(lower alkyl)carbamoyl, N,N-di(loweralkyl)carbamoyl, amino, lower alkylamino, di(lower alkyl)amino,mercapto, lower alkylthio, lower hydroxyalkyl, lower aminoalkyl, loweralkylamino-lower alkyl, di(lower alkyl)amino-lower alkyl, lowercarboxyalkyl, carbamoyl-lower alkyl, N-(lower alkyl)carbamoyl-loweralkyl, N,N-di(lower alkyl)-carbamoyl-lower alkyl or sulpho-lower alkyl.

The monocyclic heterocyclic groups are preferably aromatic andpreferably substituted with lower alkyl, halogen, hydroxy, oxo, carboxy,carbamoyl, amino, lower alkylamino, di(lower alkyl)amino, mercapto,lower alkylthio, lower hydroxyalkyl, lower aminoalkyl, loweralkylamino-lower alkyl, di(lower alkyl)amino-lower alkyl, lowercarboxylalkyl, carbamoyl-lower alkyl, N-(lower alkyl)carbamoyl-loweralkyl, N,N-di(lower alkyl)-carbamoyl-lower alkyl or sulpho-lower alkyl.Tetrazolyl, triazolyl, thiadiazolyl and triazinyl are mentioned merelyas examples. Preferred among such groups are:

1-methyl-tetrazol-5-yl, 1-(2-hydroxyethyl)-5-tetrazolyl,

5-methyl-1,3,4-thia-diazol-2-yl, 1,2,3-thiadiazol-5-yl,

1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl,

2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl and

1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl.

The bicyclic groups are preferably aromatic. They are preferablyunsubstituted or substituted with amino, lower alkylamino, di(loweralkyl)amino, carboxy, lower alkoxycarbonyl, carbamoyl, N-(loweralkyl)carbamoyl, N,N-di-(lower alkyl)carbamoyl, lower alkyl,trifluoromethyl or 3,4-alkanediyl. They are also preferably 9-memberedand have 2 to 4 nitrogen atoms as the hetero ring members.

In a preferred embodiment, A represents lower alkylidene and n is 2, andeither m or p is zero or m and p, 1, Q is the group --NR² NR³ -- and R²and R³ are hydrogen. R⁴, R⁵ and R⁶ are preferably hydrogen. Preferably,the two --OR⁴ groups are situated in positions 3 and 4 of the phenylring.

In an especially preferred embodiment, A represents methylene orisopropylidene.

Preferred substituents in the 7-position of a cephalosporin of formula Iare as follows: ##STR3## R¹ preferably is hydrogen, lower alkyl, loweralkoxy, halogen, or the groups --CH₂ R' or --CH₂ --S--R" in which R' isazido, lower alkanoyloxy, carbamoyloxy, N-(lower alkyl)carbamoyloxy,N,N-di(lower alkyl)carbamoyloxy or a N-containing heterocyclic group isattached via a nitrogen atom, and R" is a heterocyclic group attachedvia a carbon atom.

In an especially preferred embodiment, R¹ represents the group --CH₂--S--R". R" preferably is a bicyclic, 8- to 10-membered partiallyunsaturated or aromatic heterocyclic group which contains an oxygen orsulphur atom and/or 1-5 nitrogen atoms as the hetero ring member(s). Theheterocyclic group R" in this case is preferably unsubstituted or mono-,di- or trisubstituted with amino, lower alkyl, lower alkoxy, loweralkanediyl, halogen, trifluoromethyl, hydroxy, oxo, carboxy, loweralkoxycarbonyl, carbamoyl, N-(lower alkyl)carbamoyl or N,N-di(loweralkyl)carbamoyl.

In an especially preferred embodiment, the heterocyclic group R" has theformula ##STR4## wherein R¹⁰ is hydrogen, amino, carboxy, loweralkoxycarbonyl, carbamoyl, hydroxymethyl, N-(lower alkyl)carbamoyl orN,N-di(lower alkyl)-carbamoyl and R¹¹ and R¹² each are hydrogen, loweralkyl or trifluoromethyl or together represent a 3,4-alkanediyl group.

The heterocyclic groups of formulae (a) and (b) are preferably linkedvia the 5- or the 7-position, especially via the 7-position. Theheterocyclic group of formula (c) is preferably linked via the 5- or7-position, especially via the 5-position, and that of formula (d) ispreferably linked via the 5- or 8-position, especially via the5-position. The substituent R¹⁰ is preferably situated in the 3-positionwhen the heterocyclic group corresponds to formula (a), (c) or (d); R¹⁰preferably is carbamoyl or hydroxymethyl; R¹¹ preferably is hydrogen;and R¹² is preferably lower alkyl or trifluoromethyl, especially methyl.

In further especially preferred embodiments, R" is2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl or2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyridin-7-yl.

R preferably is 2-amino-4-thiazolyl.

Examples of compounds within the scope of the present invention, whichare especially preferred, are the following:

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, and

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

as well as their pharmaceutically acceptable salts.

Additional compounds in accordance with the invention are the followingand their pharmaceutically acceptable salts:

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-3-(acetoxymethyl)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]]-3-[[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

1-[(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-2carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-yl]pyridiniumbetaine,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-[(3,4-dihydroxyphenyl)sulphonyl]carbazolyl]-1-methylethoxy]imino]acetamido]-3-[[(2-carbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,8-bis(trifluoromethyl)-4-quinolinyl]thio]methyl-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylicacid, and

3[[[(6R,7R)-7-[(Z)-2-(2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-3-yl]methyl]thio]-1-(carbamoylmethyl)pyridiniumbetaine.

The compounds of formula I form pharmaceutically acceptable salts withbases. Examples of salts of compounds of formula I are the alkali metalsalts, for example, the sodium and potassium salts, the ammonium salts,the alkaline earth metal salts, for example, calcium salts, the saltswith organic bases, for example, with amines such as diisopropylamine,benzylamine, dibenzyl-amine, triethanolamine, triethylamine,N,N-dibenzyl-ethylenediamine, N-methylmorpholine, pyridine, piperazine,N-ethylpiperidine, N-methyl-D-glucamine and procaine or with amino acidssuch as arginine and lysine. Mono-, di-, and tri-salts can result,depending on the number of acidic groups in the compounds of formula I.

The compounds of formula I, which have a basic substituent, also forminternal salts and acid addition salts with organic and inorganic acids.Examples of acid addition salts of compounds of formula I are salts withmineral acids, for example, hydrohalic acids such as hydrochloric acid,hydrogen bromide and hydrogen iodide, sulphuric acid, nitric acid,phosphoric acid and the like, salts with organic sulphonic acids, forexample, with alkyl- and arylsulphonic acids such as ethanesulphonicacid, p-toluenesulphonic acid, benzenesulphonic acid, and the like, aswell as salts with organic carboxylic acids, for example, with aceticacid, tartaric acid, maleic acid, citric acid, benzoic acid, salicyclicacid, ascorbic acid, and the like.

The pharmaceutically acceptable salts can be prepared according toconventional methods known to those skilled in the art.

The readily hydrolyzable esters of the compounds of formula I are,preferably, esters which can be hydrolyzed under mild conditions,especially those which can be hydrolyzed under physiological conditions,for example, enzymatically. Examples of such esters, are the 1-(loweralkanoyloxy)-lower alkyl esters, e.g., the acetoxymethyl,pivaloyloxymethyl, 1-acetoxyethyl and the 1-pivaloyloxyethyl esters, the1-(lower alkoxycarbonyloxy)-lower alkyl esters, e.g., the(methoxycarbonyloxy)methyl, 1-(ethoxycarbonyloxy)ethyl and the1-(isopropoxycarbonyloxy)ethyl esters, the lactonyl esters, e.g., thephthalidyl and thiophthalidyl esters, the 1-(lower alkoxy)-lower alkylesters, e.g., the methoxy-methyl esters, the 1-(loweralkanoylamino)-lower alkyl esters, e.g., the acetamidomethyl esters, thebenzyl esters, the cyanomethyl esters, and the(2-oxo-1,3-dioxol-4-yl)methyl esters.

Additional carboxy groups which may be present in a compound of formulaI can also be present in the form of readily hydrolyzable ester groups.These readily hydrolyzable esters of the compounds of formula I can beprepared according to procedures which are familiar to those skilled inthe art.

The compounds of this invention can be hydrated. Such hydrates can beobtained in situ during the course of the manufacturing process or as aconsequence of hygroscopic properties of an initially anhydrous product.Alternatively, a wholly or partially anhydrous product can be exposed toa moist atmosphere.

Compounds in accordance with the invention, i.e., the compounds offormula I above, their readily hydrolyzable esters and pharmaceuticallyacceptable salts as well as the hydrates of these compounds, esters andsalts, can be prepared by the following procedures:

a) acylating a compound of the formula ##STR5## wherein R¹ is as definedabove, or a readily hydrolyzable ester thereof or an acid addition saltof one of these compounds with a compound of the formula ##STR6##wherein R, R⁴, R⁵, R⁶, A, Q, m, n and p have the above meanings, or

b) reacting a compound of the formula ##STR7## wherein R and R¹ have theabove meanings, or a readily hydrolyzable ester thereof, optionally inthe presence of a copper salt, with a compound of the formula ##STR8##wherein R⁴, R⁵, R⁶, A, Q, m, n and p have the above meanings,

or with an acid addition salt thereof, or

c) alkylating a compound of the formula ##STR9## wherein R and R¹ havethe above meanings or a readily hydrolyzable ester thereof with acompound of the formula ##STR10## wherein X represents a leaving groupand R⁴, R⁵, R⁶, A, Q, m, n and p have the above meanings, or

d) reacting a compound of the formula ##STR11## wherein R^(o) representsa group which is removable by hydrolysis and R, R¹ and A have the abovemeanings,

with a compound of the formula ##STR12## wherein Q' represents the group--NR² -- or --NR² NR³ -- and R², R³, R⁴, R⁵, R⁶ and n have the abovemeanings, or

e) reacting a compound of the formula ##STR13## wherein R^(o), R, R¹, A,Q' and p have the above meanings, with a reactive derivative of asulphonic acid of the formula ##STR14## wherein R⁴, R⁵ and R⁶ have theabove meanings, or

f) reacting a compound of the formula ##STR15## wherein Q" representslower alkylene or C₃₋₇ -cycloalkylene which is optionally substitutedwith carboxy, carbamoyl, lower alkylcarbamoyl or di(loweralkyl)-carbamoyl and R⁰, R, R¹, A, p, m and X have the above meanings,

either in the presence of a base with a sulphinic acid or a mercaptan ofthe formula ##STR16## wherein R⁴, R⁵ and R⁶ have the above meanings, orwith a salt thereof, or

g) reacting a compound of the formula ##STR17## wherein R, R⁴, R⁵, R⁶,A, Q, X, m, n and p have the above meanings,

or a readily hydrolyzable ester thereof with a compound of the formula

    HS--R"                                                     XVI

wherein R" is a heterocyclic group which is attached via a carbon atom,or

h) if desired, hydrolyzing a readily hydrolyzable ester of a compound offormula I and

i) if desired, converting a product thus obtained into apharmaceutically acceptable salt or a hydrate.

In the above processes, any reactive amino, hydroxyl or carboxy groupswhich may be present must be blocked by protecting groups. Theseinstances are readily recognizable by those skilled in the art and,also, the selection of suitable protecting groups will be apparent tohim.

Further, it is possible that products in accordance with the inventionoccur as mixtures with the corresponding isomeric products. Thus, forexample, one can obtain oximes having the [E]-configuration or Δ²-isomers of cephalosporan derivatives in accordance with the invention.The separation of these byproducts as well as their recycling toproducts in accordance with the invention can be effected according tomethods which are known to those skilled in the art, for example, usingchromatographic and crystallization methods.

Acylation in accordance with process variant (a) can be carried outaccording to known methods. For example, the compound of formula II canbe acylated using the free carboxylic acid of formula III or a saltthereof with a base, with acylation being carried out in the presence ofa suitable condensation agent and the compound of formula II being firstconverted into a readily hydrolyzable ester. Suitable condensationagents are, for example, N,N'-disubstituted carbodiimides such asN,N'-dicyclohexylcarbodiimide which are preferably used together withN-hydroxybenzotriazole or N-hydroxysuccinimide, 2-halopyridinium saltssuch as 2-chloro-1-methylpyridinium chloride, phosphorus oxychloride,thionyl chloride and oxalyl chloride.

It is also possible to use the carboxylic acid of formula III in theform of a reactive derivative. Suitable reactive derivatives includeacid chlorides, acid anhydrides, mixed anhydrides (for example,anhydrides with trifluoroacetic acid, benzenesulphonic acid,mesitylenesulphonic acid, p-toluenesulphonic acid and p-chlorosulphonicacid) and active thiol esters, for example,S-(2-benzothiazolyl)-thioesters.

If desired, the acylation can be carried out in the presence of anacid-binding agent, such as sodium hydrogen carbonate, potassiumcarbonate, triethylamine, pyridine or N-methylmorpholine. Suitablesolvents are, for example, cyclic ethers such as tetrahydrofuran anddioxan, halogenated lower hydrocarbons such as chloroform and methylenechloride, dimethylformamide, dimethylacetamide, acetonitrile, acetoneand water, as well as mixtures thereof. The reaction temperature canvary within a wide range, typically between -50° C. and 50° C., andperferably between about -10° C. and 30° C.

Oxime formation in accordance with process variant (b) can also becarried out according to known methods. The compound of formula V ispreferably used in the form of an acid addition salt, for example, asthe hydrochloride or as the p-toluenesulphonate. Suitable solvents are,for example, water, lower alcohols such as methanol, cyclic ethers suchas tetrahydrofuran and dioxan, acetonitrile, dimethylformamide anddimethylacetamide, as well as mixtures thereof. In a preferredembodiment, dimethylacetamide is used as the solvent. In a furtherpreferred, embodiment the reaction is carried out in the presence of acopper salt, with both copper(I) salts and copper(II) salts beingsuitable. Suitable salts are, for example, the corresponding halides,e.g., chlorides and bromides, sulphates, acetates, nitrates, oxides,carbonates, perchlorates and the tetrafluoroborates. The reactiontemperature is in the range from -20° C. to 40° C., preferably 0° C. to30° C.

Alkylation in accordance with process variant (c) can also be carriedout according to known methods. For example, the compounds of formulaeVI and VII can be reacted with one another in the presence of aninorganic or organic base and in an inert organic solvent, preferably inan aprotic solvent. Suitable bases are, for example, potassiumcarbonate, sodium hydride or tertiary amines such as triethylamine.Suitable solvents are dimethylformamide, dimethylacetamide, dimethylsulphoxide and acetone, as well as mixtures thereof.

It is, however, also possible to convert the oxime of formula VI with astrong base, such as sodium or lithium hydride, into the correspondingsodium or lithium salt and then to react this with the compound offormula VII. The solvents mentioned above are also suitable for thisprocedure.

The leaving group denoted by X is preferably a halogen atom, forexample, a chlorine, bromine or iodine atom, or an arylsulphonyloxygroup, for example, the p-toluenesulphonyloxy group. The reaction isusually carried out at temperatures between -70° C. and 60° C.,preferably between -20° C. and 20° C.

Readily hydrolyzable esters of the compounds of formula I in which p andm are the number 1, Q is the group --NR² -- or --NR² NR³ --, and R² andR³ and the remaining substituents have the same meanings as above can beprepared in accordance with process variant (d). This process can alsobe carried out according to known methods. For example, the samereaction conditions as given above for process variant (a) can be used.

Readily hydrolyzable esters of the compounds of formula I in which m is1, n is 2 and Q is the group --NR² -- or --NR² NR³ --, and R², R³ andthe remaining substituents have the same meanings as above can beprepared in accordance with variant (e). This process can also becarried out according to known methods. A sulphonic acid halide,especially a sulphonic acid chloride, is preferably used as the reactivesulphonic acid derivative. The reaction is preferably carried out in thepresence of a base, e.g., a tertiary amine such as triethylamine.Suitable solvents are, for example, cyclic ethers such astetrahydrofuran and dioxan, open-chain ethers such as diethyl ether,halogenated lower hydrocarbons such as chloroform and methylenechloride, dimethylformamide, dimethylacetamide, acetonitrile andacetone. The reaction can be carried out at a temperature in the rangefrom -50° C. to 50° C., preferably between -10° C. and 30° C.

Readily hydrolyzable esters of compounds of formula I in which Q islower alkylene or C₃₋₇ -cyclo-alkylene which is optionally substitutedwith carboxy, carbamoyl, lower alkylcarbamoyl or di(loweralkyl)-carbamoyl and n is zero or 1 and the remaining substituents havethe above meanings, can be prepared in accordance with variant (f). Thisprocess can also be carried out according to methods which are known.For instance, the reaction can be carried out in an inert solvent, forexample, a halogenated lower hydrocarbon such as methylene chloride andchloroform, in a cyclic ether such as tetrahydrofuran or dioxan, in anopen-chain ether such as diethyl ether, in dimethylformamide,dimethylacetamide, dimethyl sulphoxide or in acetone, in the presence ofa base such as potassium carbonate or a tertiary amine such astriethylamine. It is, however, also possible to use the sulphinic acidof formula XIII or the mercaptan of formula XIV in the form of a salt,with the lithium, sodium and potassium salts being especially preferredfor this purpose. The reaction can be carried out over a widetemperature range, but preferably at room temperature.

Compounds of formula I in which R¹ is the group --CH₂ --S--R" and R" isa heterocyclic group attached via a carbon atom and the remainingsymbols have the above meanings can be prepared in accordance withvariant (g). This process can also be carried out according to methodswhich are known. The leaving group denoted by X is preferably a halogenatom, e.g., chlorine, bromine or iodine, a lower alkyl- orarylsulphonyloxy group such as methanesulphonyloxy orp-toluenesulphonyloxy, or a lower alkanoyloxy group such as acetoxy. Thesymbol X preferably signifies acetoxy. The reaction can be carried out,for example, under the same conditions as are described above forprocess variant (f).

For the preparation of the readily hydrolyzable esters of the carboxylicacids of formula I in accordance with variant (h), the carboxylic acidis preferably reacted with the corresponding halide containing the estergroup, preferably with the iodide. The reaction can be accelerated withthe aid of a base, e.g., an alkali metal hydroxide or carbonate, or anorganic amine such as triethylamine. This reaction is preferably carriedout in an inert organic solvent such as dimethylacetamide,hexamethylphosphoric acid triamide, dimethyl sulphoxide or, preferably,dimethylformamide. The temperature preferably lies in the range fromabout 0° to 40° C.

The preparation of the salts and hydrates of the compounds of formula Iand, respectively, of the hydrates of these salts in accordance withvariant (i) can be effected in a manner known per se, e.g., by reactingthe carboxylic acid of formula I or a salt thereof with an equivalentamount of the desired base, conveniently in a solvent such as water orin an organic solvent such as ethanol, methanol, acetone or many others.Correspondingly, salt formation is brought about by the addition of anorganic or inorganic acid. The temperature of the salt formation is notcritical. In general it is at room temperature, but it can also beslightly over or under, for example, in the range from 0° C. to +50° C.

The preparation of the hydrates occurs for the most part in situ duringthe course of the manufacturing process or as a consequence of thehygroscopic properties of an initially anhydrous product. Alternatively,a completely or partially anhydrous product (carboxylic acid of formulaI or ester or salt thereof) can be exposed to a moist atmosphere, e.g.,at about +10° C. to +40° C.

The various compounds which are used as starting materials are known orcan be prepared according to known methods and starting from knownstarting materials. The Examples below contain detailed informationconcerning the preparation of starting materials.

As already mentioned, the compounds in accordance with the invention areuseful as antibiotics, and they possess a broad spectrum of activityagainst both Gram-positive and Gram-negative microorganisms.

To illustrate the antimicrobial activity of compounds in accordance withthe invention, various compounds prepared in accordance with the workingExamples hereinafter were tested for their activity in vitro. Theactivities (Minimum Inhibitory Concentration in μg/ml) ascertained arecompiled in the following Table:

                                      TABLE I                                     __________________________________________________________________________              End product from Example                                            Organism  1    2    3    5   6   7   8   9    10                              __________________________________________________________________________    E. coli 25922                                                                           <0.06                                                                              <0.06                                                                              <0.06                                                                              <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                              0.12                            E. coli TEM 1                                                                           <0.06                                                                              <0.06                                                                              <0.06                                                                              <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                              <0.06                           K. pneumoniae 418                                                                       <0.06                                                                              <0.06                                                                              <0.06                                                                              <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                             <0.06                                                                              <0.06                           K. oxytoca 1082 E                                                                       0.25 0.12 <0.06                                                                              <0.06                                                                             1   <0.06                                                                              0.12                                                                             0.12 0.12                            E. cloacae 15 M                                                                         0.12 0.12 0.25 <0.06                                                                             <0.06                                                                             <0.06                                                                             --  0.5  1                               S. marcescens 80315                                                                     0.12 <0.06                                                                              <0.06                                                                              <0.06                                                                              0.12                                                                             <0.06                                                                             <0.06                                                                             0.12 0.25                            P. mirabilis 2117                                                                       0.12 0.12 0.12 <0.06                                                                             <0.06                                                                              0.12                                                                              0.12                                                                             0.25 0.12                            P. vulgaris 1028                                                                        0.12 0.12 0.12 <0.06                                                                              0.25                                                                              0.12                                                                             <0.06                                                                             0.12 0.25                            P. aeruginosa BA                                                                        0.25 0.25 0.25  0.12                                                                             1    0.25                                                                              0.25                                                                             1    0.5                             S. pyogenes B15                                                                         0.25 0.25 0.25 1   2    0.5                                                                               0.25                                                                             0.5  2                               M. morganii 6H-137I                                                                     0.25 0.25 1     0.25                                                                             <0.06                                                                              0.5                                                                              <0.06                                                                             0.25 0.5                             C. freundii 902                                                                         0.25 0.25 0.25  0.12                                                                              0.12                                                                              0.12                                                                             <0.06                                                                             0.25 0.25                            __________________________________________________________________________

                  TABLE II                                                        ______________________________________                                                       End product from                                                              Example                                                        Organism         7        15                                                  ______________________________________                                        E. coli 25922    0.12     <0.06                                               E. coli TEM 1    <0.06    <0.06                                               K. pneumoniae 418                                                                              <0.06    <0.06                                               K. oxytoca 1082 E                                                                              0.25     0.5                                                 E. cloacae 15 M  0.5      0.5                                                 S. marcescens 80315                                                                            <0.06    <0.06                                               P. mirabilis 2117                                                                              0.25     0.12                                                P. vulgaris 1028 0.25     0.12                                                P. aeruginosa BA 0.25     0.12                                                S. pyogenes B15  0.5      0.5                                                 M. morganii 6H-1371                                                                            0.5      0.25                                                C. freundii 902  0.25     0.12                                                ______________________________________                                         < means less than                                                        

The compounds in accordance with the invention can be used in the formof pharmaceutical preparations for enteral or parenteral administration.These compounds can be administered, for example, perorally, such as inthe form of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions; rectally, such as in theform of suppositories; or parenterally, such as in the form of injectionsolutions.

The preparation of such pharmaceutical dosage forms can be effectedusing conventional techniques familiar to those skilled in the art bycombining the antibacterial compound with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, the usual pharmaceutical adjuvants.

As such carrier materials there are suitable not only inorganic carriermaterials, but also organic carrier materials. Thus, there can be usedas carrier materials for tablets, coated tablets, dragees and hardgelatine capsules materials such as, for example, lactose, maize starchor derivatives thereof, talc, stearic acid or its salts. Suitablecarriers for soft gelatine capsules are, for example, vegetable oils,waxes, fats and semi-solid and liquid polyols (depending on the natureof the active substance; no carriers are, however, required in the casesoft gelatine capsules). Suitable carrier materials for the preparationof solutions and syrups are, for example, water, polyols, saccharose,invert sugar and glucose. Suitable carrier materials for injectionsolutions are, for example, water, alcohols, polyols, glycerine andvegetable oils. Suitable carrier materials for suppositories are, forexample, natural or hardened oils, waxes, fats and semi-liquid or liquidpolyols.

As pharmaceutical adjuvants there come into consideration the usualpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweetners, colorants, flavorants, salts for varying the osmoticpressure, buffers, coating agents and antioxidants.

The compounds of formula I and their salts and, respectively, hydratesare especially useful for parenteral application and for this purposeare preferably provided as lyophilizates or dry powders for dilutionwith usual carriers such as water or isotonic saline. The readilyhydrolyzable esters of compounds of formula I and their salts andhydrates are especially useful for enteral application.

The pharmaceutical compositions can contain the antibacterial compoundsin accordance with the invention in therapeutically effective amounts ofabout 25-2000 mg, preferably 100-1000 mg, per unit dosage form. Foradults, a daily dosage of about 0.05 g to about 4 g, especially about0.1 g to about 2 g, is usually appropriate.

The following Examples are intended to illustrate the present inventionin more detail, but are not intended to limit its scope in any manner.All temperatures are given in degrees Celsius.

EXAMPLE 1

In a first flask, a solution of 74 mg of 2-amino-4-thiazoleglyoxylicacid (Z)-O-[[(3,4-dihydroxyphenyl)-sulphonyl]methyl] oxime in 1 ml ofN,N-dimethylformamide was treated with 83 mg of N,O-bis-(trimethylsilyl)acetamide and stirred at 20° C. for 15 minutes. The solution was cooledto 0° C. and treated in succession with 39 mg of 1-hydroxy-benzotriazoleand 51 mg of N,N'-dicyclohexylcarbodiimide. The reaction mixture wasstirred at 0° C. for 1 hour, whereby a precipitate formed.

In a second flask, 64 mg of (7R)-7-aminocephalosporanic acid and 124 mgof N,O-bis-(trimethylsilyl)acetamide in 1 ml of N,N-dimethylformamidewere stirred at 20° C. for 20 minutes. A clear solution was obtainedwhich was added at 0° C. to the solution in the first flask. Thereaction mixture was stirred at 0° C. for 1 hour and at 20° C. for 2hours. The precipitate was filtered off under suction and the filtratewas partitioned between 2% aqueous sodium hydrogen carbon solution andethyl acetate. The aqueous phase was adjusted to pH 7 with 3Nhydrochloric acid, concentrated in a vacuum to a volume of about 5 mland the concentrated solution was chromatographed on MCI gel CHP2OP(Mitsubishi Chemical Industries Ltd.). Elution was carried out firstwith 1% aqueous acetic acid and then with mixtures of 1% aqueous aceticacid/methanol, using increasing amounts of methanol. By lyophilizationof the product fractions, which were concentrated in a vacuum, there wasobtained(6R,7R)-3-(acetoxymethyl)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.03 (s, 3H); 3.56 (d, J=22 Hz, 1H, signal of thecoupling partner overlapped by the H₂ O signal at 3.45); 4.70 (d, J=12.5Hz, 1H); 4.99 (d, J=12.5 Hz, 1H); 5.08 (d, J=5 Hz, 1H); 5.17 (d, J=12.5Hz, 1H); 5.25 (d, J=12.5 Hz, 1H); 5.69 (dd, J=8 and 5 Hz, 1H); 6.72 (s,1H); 6.90 (d, J=8 Hz, 1H); 7.19 (d, J=1 Hz, 1H); 7.22 (dd, J=8 and 1 Hz,1H); 7.32 (broad s, 2H); 9.66 (broad d, J=8 Hz, 1H) ppm.

The 2-amino-4-thiazoleglyoxylic acid(Z)-O-[[(3,4-dihydroxyphenyl)sulphonyl]methyl] oxime used as thestarting material was prepared as follows:

a) 135 ml of a 1.7M butyllithium/n-hexane solution were added dropwisewithin 3 minutes to 220 ml of diethyl ether pre-cooled to -40° C. Thesolution was cooled to -50° C. and then treated within 5 minutes with asolution of 50.4 g of 5-bromo-2,2-dimethyl-1,3-benzodioxol in 100 ml ofdiethyl ether, upon which the temperature rose to -35° C. The reactionsolution was warmed to -10° C. and stirred at this temperature for 30minutes. Then, 6.6 g of sulphur were introduced in portions into thereaction solution, which had been cooled to -60° C. The temperature thenrose to -25° C. The reaction mixture was stirred at 0° C. for a further15 minutes. 34 g of methyl iodide were then added and the reactionmixture was stirred at 0° C. for 1 hour. The reaction solution wasdiluted with ethyl acetate and washed in succession with 200 ml of 2Naqueous sodium hydroxide solution and 200 ml of water. The organic phasewas dried over sodium sulphate and the solvent was removed in a vacuum.The residual oil was fractionated in a vacuum over a 60 cm long Vigreuxcolumn. There was obtained 2,2-di-methyl-5-(methylthio)-1,3-benzodioxolas a colorless oil having a boiling point of 80°-83° C. (20 Pa).

b) A solution of 19.6 g of 2,2-dimethyl-5-(methylthio)-1,3-benzodioxolin 500 ml of methylene chloride was treated at 0° C. with 20.3 g of 85%m-chloroperbenzoic acid. The mixture was subsequently stirred at 0° C.for 1 hour. A white precipitate resulted. The reaction mixture wasextracted with 400 ml of 17% aqueous sodium carbonate solution and 400ml of water. The organic phase was dried over sodium sulphate and freedfrom solvent in a vacuum. The residue was taken up in a small amount ofmethylene chloride and chromatographed on silica gel, with elution beingcarried out with ethyl acetate/n-hexane/methylene chloride (1:1:1,v/v/v). After crystallization from ethyl acetate/n-hexane, there wasobtained 2,2-dimethyl-5-(methyl-sulphinyl)-1,3-benzodioxol as whitecrystals having a melting point of 87°-88° C.

c) To a solution, cooled to 0° C., of 16.5 g of2,2-di-methyl-5-(methylsulphinyl)-1,3-benzodioxol and 6.2 g of pyridinein 230 ml of methylene chloride, there were added in succession 5.43 gof bromine and 12.1 g of N-bromosuccin-imide. The reaction mixture wasstirred at 0° C. for 3 hours and then at 20° C. for a further 12 hours.The orange colored solution was cooled to 0° C., treated with 40 ml of1M aqueous sodium sulphite solution and the pH of the mixture wasadjusted to 7 by the addition of 17% aqueous sodium carbonate solution.After stirring for 10 minutes, the phases were separated. The organicphase was washed in succession with 50 ml of 1N aqueous hydrochloricacid, 50 ml of 5% sodium hydrogen carbonate solution and 3 times with100 ml of water each time, dried over sodium sulphate and evaporated ina vacuum. The residue was chromatographed on silica gel, with elutionbeing carried out with ethyl acetate/hexane (1:2, v/v). Aftercrystallization from acetone/water, there was obtained5-[(bromomethyl)-sulphinyl]-1,3-benzodioxol as white crystals having amelting point of 88°-89° C.

d) A mixture of 8.73 g of5-[(bromomethyl)sulphinyl]-2,2-dimethyl-1,3-benzodioxol, 6.45 g of(Z)-2-[amino-α-(hydroxyimino)]-4-thiazoleacetic acid ethyl ester and4.97 g of potassium carbonate in 36 ml of dimethyl sulphoxide wasstirred at 75° C. for 2 hours. After cooling, the reaction mixture wasdiluted with 100 ml of ethyl acetate and extracted 4 times with 50 ml of5% aqueous sodium chloride solution each time. The organic phase wasdried over sodium sulphate and freed from solvent in a vacuum. Theresidue was taken up in 60 ml of methylene chloride. Undissolvedmaterial was separated by filtration and the filtrate was treated at 20°C. with 9.4 g of 55% m-chloroperbenzoic acid. The reaction mixture wasstirred at 20° C. for 1 hour, then diluted with methylene chloride andwashed in succession with 17% aqueous sodium carbonate solution andwater. The organic phase was dried over sodium sulphate and freed fromsolvent in a vacuum. The residue was chromatographed on silica gel. Amixture of ethyl acetate/n-hexane (1:1, v/v) eluted the product, whichwas crystallized from ethyl acetate/n-hexane. There was obtained2-amino-4-thiazoleglyoxylic acid ethyl ester(Z)-O-[[[(3,4-(isopropylidenedioxy)phenyl]sulphonyl]methyl] oxime aswhite crystals having a melting point of 160°-161° C.

e) A solution of 441 mg of 2-amino-4-thiazoleglyoxylic acid ethyl ester(Z)-O-[[[(3,4-(isopropylidenedioxy)-phenyl]sulphonyl]methyl] oxime in 5Methanolic hydrochloric acid was heated to 80° C. for 3 hours. Thereaction solution was suction filtered and the solvent was removed in avacuum. The residue was taken up in 2 ml of ethanol and 2 ml of 2Naqueous sodium hydroxide solution. The dark solution obtained wasstirred at 20° C. for 30 minutes. 4 ml of water were then added and thepH was adjusted to 7 with 3N aqueous hydrochloric acid. The solution wasconcentrated to about 3 ml in a vacuum and then chromatographed on MCIgel CHP20P. Elution was carried out first with 2% aqueous acetic acid,then with water/methanol mixtures, using greater and greater amounts ofmethanol. The product was eluted with water/methanol (9:1, v/v) and thencrystallized from methanol/diethyl ether. There was thus obtained2-amino-4-thiazoleglyoxylic acid(Z)-O-[[(3,4-dihydroxyphenyl)sulphonyl]-methyl] oxime as white crystalshaving a melting point of 167° C. (dec.).

¹ H NMR (DMSO-d₆): δ5.24 (s, 2H); 6.73 (s, 1H); 6.88 (d, J=8 Hz, 1H);7.19 (dd, J=8 and 1 Hz, 1H); 7.23 (d, J=1 Hz, 1H); 7.26 (s, 2H); 9.79(broad s, 1H); 10.15 (broad s, 1H) ppm.

EXAMPLE 2

The procedure of Example 1 was repeated, but substituting for the(7R)-7-aminocephalosporanic acid an equimolar amount of (6R,7R)-7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid. There was obtained, after chromatographic purification on MCI geland lyophilization of the product fractions, (6R,7R)-7-[(Z)-2-(amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.68 (s, 3H); 3.44 (d, J=19 Hz, 1H); 3.66 (d, J=19Hz, 1H); 4.20 (d, J=13 Hz, 1H); 4.52 (d, J=13 Hz, 1H); 5.06 (d, J=5 Hz,1H); 5.14 (d, J=12.5 Hz, 1H); 5.21 (d, J=12.5 Hz, 1H); 5.64 (dd, J=8 and5 Hz, 1H); 6.70 (s, 1H); 4.89 (d, J=8 Hz, 1H); 7.19 (d, J=1 Hz, 1H);7.21 (dd, J=8 and 1 Hz, 1H); 7.30 (s, 2H) ppm.

EXAMPLE 3

The procedure of Example 1 was repeated, but substituting for the(7R)-7-aminocephalosporanic acid an equimolar amount of (6R,7R)-7-amino-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid. There was thus obtained, after chromatographic purification on MCIgel and lyophilization of the product fractions, (6R,7R)-7-[(Z)-2-(amino-4-thiazolyl)-2-[[[(3,4-dihyroxyphenyl)sulphonyl]-methoxy]imino]acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ3.45 (d, J=19 Hz, 1H); 3.61 (d, J=19 Hz, 1H); 3.91(d, J=14 Hz, 1H); 4.36 (d, J=14 Hz, 1H); 5.10 (d, J=5 Hz, 1H); 5.16 (d,J=13 Hz, 1H); 5.24 (d, J=13 Hz, 1H); 5.76 (dd, J=8 and 5 Hz, 1H); 6.69(s, 1H); 6.92 (d, J=9 Hz, 1H); 7.20 (m, 2H); 7.31 (s, 2H); 9.69 (s, 1H);9.76 (d, J=8 Hz, 1H); 10.12 (s, 1H) ppm.

EXAMPLE 4

The procedure of Example 1 was repeated, but substituting for the(7R)-7-aminocephalosporanic acid an equimolar amount of1-[[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-3-yl]methyl]pyridiniumbetaine hydrochloride. There was obtained, after chromatographicpurification on MCI gel and lyophilization of the product fractions,1-[(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-yl]pyridiniumbetaine as a white powder.

¹ H NMR (DMSO-d₆): δ inter alia 2.97 (d, J=18 Hz, 1H); 3.46 (d, J=18 Hz,1H); 6.67 (s, 1H); 6.89 (d, J=8 Hz, 1H); 7.18 (m, 2H); 7.29 (broad s,2H) ppm.

EXAMPLE 5

In a first flask, a solution of 52 mg of 2-amino-4-thiazoleglyoxylicacid (Z)-O-[[(3,4-dihydroxyphenyl)-sulphonyl]methyl]oxime in 0.7 ml ofN,N-dimethylformamide was cooled to 0° C. and treated with 27 mg of1-hydroxybenzotriazole and 36 mg of N,N'-dicyclohexylcarbodiimide. Thereaction mixture was stirred at 0° C. for 1 hour, upon which aprecipitate formed.

In a second flask, 74 mg of(6R,7R)-7-amino-3-[[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 86 mg of N,O-bis(trimethylsilyl)-acetamide in 0.7 ml ofN,N-dimethylformamide were stirred at 20° C. for 30 minutes. Thereresulted a clear solution which was added at 0° C. to the solution inthe first flask. The reaction mixture was stirred at 20° C. for 2 hoursand then partitioned between ethyl acetate and 2% aqueous sodiumhydrogen carbonate solution. The aqueous phase was adjusted to pH 7 with3N aqueous hydrochloric acid, concentrated in a vacuum to a volume ofabout 5 ml, and the concentrated solution was chromatographed on MCI gelCHP2OP. Elution was carried out first with 1% acetic acid and later withmixtures of 1% aqueous acetic acid/methanol, using increasing amounts ofmethanol. By lyophilization of the product fractions, which had beenconcentrated in a vacuum, there was obtained(6R,7R)-7-[(Z)-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.62 (s, 3H); 3.53 (d, J=19 Hz, 1H); 3.74 (d, J=19Hz, 1H); 4.38 (d, J=13 Hz, 1H); 4.47 (d, J=13 Hz, 1H); 5.12 (d, J=5 Hz,1H); 5.15 (d, J=12 Hz, 1H); 5.23 (d, J=12 Hz, 1H); 5.75 (dd, J=8 and 5Hz, 1H); 6.69 (s, 1H); 6.92 (d, J=9 Hz, 1H); 7.20 (m, 2H); 7.30 (broads, 2H); 7.45 (s, 1H); 9.68 (broad s, 1H); 9.72 (d, J=8 Hz, 1H); 10.14(broad s, 1H) ppm.

EXAMPLE 6

37 mg of 2-amino-4-thiazoleglyoxylic acid(Z)-O-[[(3,4-dihydroxyphenyl)-sulphonyl]methyl]oxime were reacted with47 mg of(6R,7R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid according to the procedure described in Example 5. The productfractions obtained upon chromatography on MCI gel according to themethod described in Example 1 were concentrated and the pH of solutionthus obtained was adjusted to 7 with dilute sodium hydroxide solution.By lyophilization, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid disodium salt as a pale yellow powder.

¹ H NMR (DMSO-d₆): δ inter alia 4.91 (d, J=5 Hz, 1H); 5.09 (d, J=13 Hz,1H); 5.19 (d, J=13 Hz, 1H); 5.43 (m, 1H); 6.77 (s, 1H) ppm.

EXAMPLE 7

48 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were dissolved in 2ml of 1N ethanolic hydrochloric acid and the solution was concentratedcompletely in a vacuum. The residue was dissolved in 3 ml of ethanol andthe solvent was removed completely in a vacuum. The crude hydrochloridewas dissolved in 0.5 ml of N,N-dimethylacetamide together with 90 mg of(6R,7R)-7-(2-amino-4-thiazolegyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and the solution was stirred at room temperature for 64 hours. Thereaction solution was treated slowly at 20° C. with 5 ml of water. Aprecipitate formed, which was filtered off under suction. Forpurification, the crude product was dissolved in 3 ml of water by theaddition of a small amount of 1N sodium hydroxide solution and thenchromatographed on MCI gel CHP2OP (Mitsubishi Chemical Industries,Ltd.). Elution was carried out first with 1% aqueous acetic acid andthen with mixtures of 1% aqueous acetic acid/methanol, using increasingamounts of methanol. By concentration and lyophilization of the productfractions, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-di-hydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.61 (s, 3H), 3.50 (d, J=18 Hz, 1H); 3.77 (d, J=18Hz, 1H); 4.38 (d, J=14 Hz, 1H); 4.43 (d, J=14 Hz, 1H); 5.14 (d, J=5 Hz,1H); 5.16 (d, J=14 Hz, 1H); 5.24 (d, J=14 Hz, 1H); 5.74 (dd, J=8 and 5Hz, 1H); 6.69 (s, 1H); 6.91 (d, J=8 Hz, 1H); 7.20 (m, 2H); 7.29 (broads, 2H); 7.41 (s, 3H); 7.88 (s, 1H); 8.17 (s, 1H); 9.67 (s, 1H); 9.72 (d,J=8 Hz, 1H); 10.12 (s, 1H) ppm.

A suspension of 373 mg of(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in 7 ml of water was treated portionwise while stirring with 91 mgof N-methyl-D-glucamine. The resulting clear solution was lyophilized.There was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid N-methyl-D-glucamine salt as a white powder.

¹ H NMR (DMSO-d₆): δ2.54 (s, 3H); 2.59 (s, 3H); 2.7-4.0 (m, about 20H);4.34 (d, J=14 Hz, 1H); 4.56 (d, J=14 Hz, 1H); 4.94 (d, J=5 Hz, 1H); 5.12(d, J=14 Hz, 1H); 5.20 (d, J=14 Hz, 1H); 5.45 (dd, J=8 and 5 Hz, 1H);6.75 (s, 1H); 6.86 (d, J=8 Hz, 1H); 7.15 (d, J=1 Hz, 1H); 7.2-7.4 (m,3H); 7.72 (s, 1H); 7.82 (s, 1H); 8.17 (s, 1H); 9.45 (d, J=8 Hz, 1H) ppm.

The 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol used as the startingmaterial in the above procedure was prepared as follows:

a) A mixture of 29.1 g of5-[(bromomethyl)sulphinyl]-2,2-dimethyl-1,3-benzodioxol, 19.6 g ofN-hydroxyphthalimide and 16.7 g of potassium carbonate in 120 ml ofdimethyl sulphoxide was stirred at 75° C. for 2 hours. After cooling thereaction mixture was diluted with 400 ml of ethyl acetate and extracted4 times with 200 ml of 5% sodium chloride solution each time. Theorganic phase was dried over sodium sulphate and freed from solvent in avacuum. The residue was dissolved in 200 ml of methylene chloride andtreated with 32 g of 55% m-chloroperbenzoic acid while cooling in an icebath. The reaction mixture was stirred at 20° C. for 1 hour, thendiluted with methylene chloride and washed in succession with 17%aqueous sodium carbonate solution and water. The organic phase was driedover sodium sulphate, the solvent was evaporated in a vacuum, and theresidual oil was crystallized from methylene chloride/hexane. There wasthus obtained N-[[(3,4-isopropylidenedioxy)-phenyl]sulphonyl]methoxy]phthalimide as whitecrystals having a melting point of 191°-193° C.

b) A suspension of 2.34 g ofN-[[(3,4-isopropylidenedioxy)phenyl]sulphonyl]methoxy]phthalimide in 10ml of ethanol was treated with 0.4 ml of hydrazine hydrate and themixture was stirred at 20° C. for 45 minutes. There first resulted aclear solution, from which a white precipitate separated later. Thereaction mixture was suction filtered, the filtrate was concentratedcompletely in a vacuum, and the residue was dissolved in 240 ml of 0.6Nhydrochloric acid. 200 ml of solvent were distilled off from thissolution at room temperature within 3 hours. The concentrated solutionwas cooled, adjusted to pH 3.5 by the addition of 2N aqueoushydrochloric acid and then chromatographed on MCI gel CHP2OP using 1%aqueous acetic acid as the eluent. The substance fractions were freedfrom solvent in a vacuum and the residue was triturated with diethylether. There was obtained 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol aspale violet crystals having a melting point of 151° C. (dec.).

The(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid used as the starting compound was be prepared as follows:

c) A suspension of 2.50 g of methyl7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate (Euro.Pat. Publ. 150,507) in 25 ml of 25 percent aqueous ammonia was stirredat room temperature for 6 hours. The mixture was filtered and the solidwas dried at 50° in a vacuum. There was obtained7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as a 1:1:1adduct with water and ammonia.

¹ H NMR DMSO-d₆): δ2.26 (s, 3H); 6.72 (s, 1H); 7.17 (s, 4H, NH₄ ⁺); 7.60(broad s, 1H); 7.84 (broad s, 1H) ppm.

d) A mixture of 5.46 g of (7R)-7-aminocephalosporanic acid and 4.85 g of7-mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidine-2-carboxamide ammoniumsalt was treated while stirring well with 50 ml of a 20 percent solutionof boron trifluoride in acetonitrile. The temperature was kept at below40° by ice bath-cooling. The reaction mixture was stirred at 20° for 1hour and subsequently diluted with 200 ml of water. A white precipitateformed, which is collected by filtration. The still-moist material wasdissolved in 50 ml of 3N HCl and the solution was filtered. A whiteproduct crystallized out from the filtrate after a short time. Byfiltration, washing with H₂ O and acetone and drying in a vacuum, therewas obtained(6R,7R)-7-amino-3[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as the hydrochloride.

¹ H NMR (DMSO-d₆): δ2.61 (s, 3H); 3.74 (d, J=17.5 Hz, 1H); 2.87 (d,J=17.5 Hz, 1H); 4.46 (d, J=12.5 Hz, 1H); 4.54 (d, J=12.5 Hz, 1H); 5.20(d, J=5 Hz, 1H); 5.25 (d, J=5 Hz, 1H); 7.43 (s, 1H); 7.89 (s, 1H); 8.19(s, 1H) ppm. MS: 422 (M+H)⁺.

IR (KBr): 1770.

e) A suspension of 1.71 g of(6R,7R)-7-amino-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid hydrochloride in 20 ml of methylene chloride was treated with 2.74ml of N,O-bis-(trimethylsilyl)acetamide. After all had dissolved intosolution, 1.32 g of 2-amino-4-thiazolethioglyoxylic acidS-(2-benzothiazolyl) ester were added and the mixture was stirred at 20°for 1.5 hours. Undissolved material was separated by filtration and thefiltrate was diluted with 40 ml of methylene chloride. Upon the dropwiseaddition of 2 ml of ethanol, a yellow precipitate formed, which wascollected by filtration and dried in a vacuum. There was obtained(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a yellow powder.

¹ H NMR (DMSO-d₆): δ2.60 (s, 3H) 3.54 (d, J=17.5 Hz, 1H); 3.74 (d,J=17.5 Hz, 1H); 4.42 (d, J=14 Hz, 1H); 4.56 (d, J=14 Hz, 1H); 5.14 (d,J=5 Hz, 1H); 5.72 (d, J=5 Hz, 1H); 7.41 (s, 2H); 7.55 (s, 1H) ppm.

EXAMPLE 8

(6R,7R)-7-(2-Amino-4-thiazolglyoxylamido)-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid was reacted with 4-[[(aminooxy)methyl]sulphonyl]pyrocatecholaccording to the procedure described in Example 7. After purification ofthe crude product using the chromatographic procedure described inExample 7 and lyophilization of the product fractions, there wasobtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.62 (s, 3H); 3.54 (d, J=18 Hz, 1H); 3.75 (d, J=18Hz, 1H); 4.34 (d, J=13 Hz, 1H); 4.44 (d, J=13 Hz, 1H); 5.15 (d, J=5 Hz,1H); 5.16 (d, J=14 Hz, 1H); 5.22 (d, J=14 Hz, 1H); 5.74 (dd, J=8 and 5Hz, 1H); 6.69 (s, 1H); 6.91 (d, J=8 Hz, 1H); 7.18-7.23 (m, 3H); 7.30(broad s, 2H); 7.49 (broad s, 1H); 7.55 (broad s, 1H); 8.48 (s, 1H);9.67 (broad s, 1H); 9.73 (d, J=8 Hz, 1H); 10.09 (broad s, 1H) ppm.

The(6R,7R)-7-(2-amino-4-thiazolglyoxylamido)-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid used as the starting compound above was prepared as follows:

a) Ethyl 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (J.Med. Chem. 1981, 24(5), 610-13) was heated in 1N aqueous sodiumhydroxide solution until all has passed into solution. The reactionmixture was cooled and its pH was adjusted to 1 with aqueoushydrochloric acid. The resulting precipitate was filtered off, dried andrecrystallized from dimethylformamide. There was obtained7-mercapto-5-methyl-pyrazolo[1,5-a] pyrimidine-3-carboxylic acid as ayellow powder having a of melting point of 161°-162° (dec.).

b) A suspension of 105 g of7-mercapto-5-methylpyrazolo-[1,5-a]pyrimidine-3-carboxylic acid in 400ml of methylene chloride was treated with 6.3 ml of1-chloro-N,N,2-trimethyl-1-propenamine and treated in an ultrasound bathuntil the majority has passed into solution. The mixture was suctionfiltered over a glass fiber filter, and ammonia was conducted into theclear filtrate at 20°. A crystalline precipitate formed which wasfiltered off under suction, dried and subsequently triturated in 100 mlof H₂ O for 5 minutes. The insoluble material was filtered off and thefiltrate was concentrated in a vacuum to half of the volume. Uponallowing to stand at 0°, there was obtained7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide as theammonium salt in the form of white crystals.

¹ H NMR (DMSO-d₆): δ2.28 (s, 3H); 6.65 (s, 1H); 7.00 (broad s, 1H); 7.17(borad s, 4H, NH₄ ⁺); 7.94 (broad s, 1H) ppm.

c) A mixture of 2.80 g of7-mercapto-5-methylpyrazolo-[1,5-a]pyrimidine-3-carboxamide ammoniumsalt and 3.38 g of (7R)-7-aminocephalosporanic acid was treated with 25ml of a 20 percent solution of boron trifluoride in acetonitrile andstirred at 20° for 40 minutes. The reaction mixture was treated with 30ml of water and the pH was adjusted to 3.5 by means 28 percent aqueoussodium hydroxide solution. The precipitate thus formed was filtered offunder suction and was chromatographed on OPTI-UP (C₁₂) (ANTEC AG,CH-Bennwil) using water as the eluent. There was obtained(6R,7R)-7-amino-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]-pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid.

¹ H NMR (DMSO-d₆): δ2.60 (s, 3H); 3.56 (d, J=17.5 Hz, 1H); 3.78 (d,J=17.5 Hz, 1H); 4.30 (d, J=12.5 Hz, 1H); 4.43 (d, J=12.5 Hz), 1H); 4.82(d, J=5 Hz, 1H); 5.04 (d, J=5 Hz, 1H); 7.20 (s, 1H); 7.50 (broad s, 1H);7.56 (broad s, 1H); 8.48 (s, 1H) ppm. IR (KBr) 1795.

d) A suspension of 2.05 g of(6R,7R)-7-amino-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in 15 ml of acetonitrile and 15 ml of water was treated with 0.69ml of triethylamine, whereupon a clear solution resulted. 2.28 g of2-amino-4-thiazolethioglyoxylic acid s-(2-benzothiazolyl) ester wereadded to this solution. After stirring at 20° for 3 hours, the reactionmixture was suction filtered and the filtrate was partitioned betweenethyl acetate and water. The aqueous phase was concentrated in a vacuumand the pH was adjusted to 2.3 with 3N hydrochloric acid, whereupon ayellow precipitate formed. After filtration, washing with water anddrying, there was obtained(6R,7R)-7-(2-amino-4-thiazolglyoxylamido)-3-[[(3-carbamoyl-5-methylpyrazolo-[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

¹ H NMR (DMSO-d₆): 2.61 (s, 3H); 3.62 (d, J=17.5 Hz, 1H); 3.82 (d,J=17.5 Hz, 1H); 4.36 (d, J=12.5 Hz, 1H); 4.47 (d, J=12.5 Hz, 1H); 5.22(d, J=5 Hz, 1H); 5.78 (dd, J=8 and 5 Hz, 1H); 7.22 (s, 1H); 7.49 (broads, 1H); 7.56 (broad s, 2H); 7.84 (s, 1H); 8.48 (s, 1H); 9.82 (d, J=8 Hz,1H) ppm.

IR(KBr) 1779.

EXAMPLE 9

(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid was reacted with 4-[[(aminoxy)methyl]-sulphonyl]pyrocatecholaccording to the procedure described in Example 7. After purification ofthe product with the chromatographic procedure in Example 7 andlyophilization of the product, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)-sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a pale yellow powder.

¹ H NMR (DMSO-d₆): δ3.56 (d, J=18 Hz, 1H); 3.73 (d, 18 Hz, 1H); 4.27 (d,J=14 Hz, 1H); 4.60 (d, J=14 Hz, 1H); 5.12 (d, J=5 Hz, 1H); 5.14 (d, J=13Hz, 1H); 5.23 (d, J=13 Hz, 1H); 5.74 (dd, J=8 and 5 Hz, 1H); 6.67 (s,1H); 6.90 (d, 8 Hz, 1H); 7.1-7.6 (m, about 6H); 7.82 (s, 1H); 8.58 (s,1H); 9.68 (s, 1H); 9.71 (d, J=8 Hz, 1H); 10.09 (s, 1H) ppm.

The(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid used as the starting compound above was prepared as follows:

a) A mixture of 11.5 g of methyl 5-aminopyrazole-4-carboxylate, 16 ml ofethyl ω,ω,ω-trifluoroacetoacetate and 150 g of polyphosphoric acid washeated to 100° while stirring for 16 hours. After cooling to 20°, coldwater was added and the mixture was extracted with ethyl acetate. Theorganic phase was washed with 1N aqueous hydrochloric acid and aqueoussaturated sodium chloride solution and then dried over Na₂ SO₄. Thesolvent was evaporated in a vacuum and the residue was taken up inether. The solid product was filtered off under suction andrecrystallized from 2-propanol. There was obtained an isomer of theproduct, namely methyl7-hydroxy-5-(trifluoromethyl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate ofm.p. 216°-217°. The product enriched in the mother liquors wascrystallized from ethyl acetate. There was obtained methyl5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate ofm.p. 149°-150°.

b) A mixture of 2.70 g of methyl5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and1.26 g of 4-dimethylaminopyridine was heated to 100° for 2.5 hours in 50ml of phosphorus oxychloride. The resulting solution was concentrated ina vacuum and then partitioned between ethyl acetate and saturated sodiumchloride solution. The organic phase was washed in succession with 1Nhydrochloric acid and saturated sodium chloride solution, dried oversodium sulphate, freed from solvent in a vacuum and the residue wascrystallized from ethyl acetate/petroleum ether. There was obtainedmethyl5-chloro-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate aswhite crystals of m.p. 126°-127°.

c) A mixture of 2.30 g of methyl5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and2.0 g of sodium hydrogen sulphide monohydrate in 60 ml of water wasstirred at 60° for 1 hour. The reaction mixture was cooled, acidifiedwith hydrochloric acid and extracted with ethyl acetate. The organicphase was washed with saturated sodium chloride solution, dried oversodium sulphate and concentrated in a vacuum until crystallizationoccurred. Petroleum ether was added and the solid product was filteredoff under suction. There was obtained methyl5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxylate.

¹ H NMR (DMSO-d₆): δ3.82 (s, 3H): 7.30 (s, 1H); 8.40 (s, 1H) ppm.

d) A solution of 1.80 g of methyl5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in800 ml of 25 percent aqueous ammonia was allowed to stand at 20° for 24hours. The solution was concentrated to a small volume in a vacuum, madeacidic with 1N hydrochloric acid, and extracted with ethyl acetate. Theorganic phase was washed with saturated sodium chloride solution, driedover sodium sulphate and evaporated in a vacuum. The residual crystalslurry was treated with petroleum ether and filtered. There was obtained5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

¹ H NMR (DMSO-d₆): δ7.28 (s, 1H); 7.62 (broad s, 1H); 8.08 (broad s,1H); 8.45 (s, 1H) ppm.

e) A mixture of 1.60 g of5-mercapto-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamideand 1.66 g of (7R)-7-aminocephalosporanic acid in 120 ml of acetonitrilewas treated while stirring with 20 ml of a 20 percent solution of borontrifluoride in acetonitrile and stirred at 20° for a further 5 hours.100 ml of water were added and the mixture was concentrated in a vacuumto a volume of about 80 ml. The pH was adjusted to 2.8 with 25 percentaqueous ammonia. After stirring for 1 hour, the precipitate obtained wasfiltered, washed in succession with water, acetone and ether and dried.There was obtained(6R,7R)-7-amino-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid.

¹ H NMR (DMSO-d₆): δ3.53 (d, J=17.5 Hz, 1H); 3.72 (d, J=17.5 Hz, 1H);4.24 (d, J=12.5 Hz, 1H); 4.58 (d, J=12.5 Hz, 1H); 4.80 (d, J=5 Hz, 1H);4.98 (d, J=5 Hz, 1H); 7.35 (broad s, 1H); 7.52 (broad s, 1H); 7.82 (s,1H); 8.57 (s, 1H) ppm.

f) A suspension of 1.425 g of(6R,7R)-7-amino-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid was treated with 0.475 ml of N,O-bis-(trimethylsilyl)acetamide.After a clear solution had been obtained, 1.20 g of2-amino-4-thiazolethioglyoxylic acid s-(2-benzothiazolyl) ester wereadded and the mixture was stirred at 20° for 2.5 hours. The reactionmixture was filtered through a glass fiber filter, the filtrate wasconcentrated in a vacuum and partitioned between ethyl acetate and 0.25Mpotassium hydrogen carbonate solution. The aqueous phase wasconcentrated in a vacuum and then chromatographed on Opti-Up (C₁₂), withelution being carried out first with water and then withwater/acetonitrile mixtures using increasing amounts of acetonitrile.The product fractions were combined, concentrated in a vacuum andadjusted to pH 2 with 3N hydrochloric acid, upon which a precipitateformed. There was obtained(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

¹ H NMR (DMSO-d₆): δ3.60 (d, J=18 Hz, 1H); 3.77 (d, J=18 Hz, 1H); 4.30(d, J=12 Hz, 1H); 4.62 (d, J=12 Hz, 1H); 5.20 (d, J=5 Hz, 1H); 5.76 (dd,J=8 Hz and J=5 Hz, 1H); 7.33 (s, 1H); 7.40 (s, 2H); 7.50 (s, 1H); 7.80(s, 1H); 7.83 (s, 1H); 8.57 (s, 1H); 9.29 (d, J=8 Hz, 1H) ppm. IR (KBr):1775

MS: 629 (M+H)⁺.

EXAMPLE 10

34 mg of(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid were reacted with 28 mg of2-[2-(aminoxy)-2-methylpropionyl]-1-[(3,4-dihydroxyphenyl)sulphonyl]hydrazineaccording to the procedure described in Example 7. After purification ofthe crude product with the chromatographic procedure described inExample 1 and lyophilization of the product, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-[(3,4-dihydroxy-phenyl)sulphonyl]carbazolyl]-1-methylethoxy]imino]aceta-mido]-3-[[(2-carbamoyl)-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ1.25 (s, 3H); 1.27 (s, 3H); 2.60 (s, 3H); 3.66 (d,J=18 Hz, 1H); 3.86 (d, J=18 Hz, 1H); 4.42 (d, J=13 Hz, 1H); 4.56 (d,J=13 Hz, 1H); 5.24 (d, J=5 Hz, 1H); 5.86 (dd, J=8 and 5 Hz, 1H); 6.79(d, J=9 Hz, 1H); 6.82 (s, 1H); 7.09 (dd, J=9 and 1.5 Hz, 1H); 7.19 (d,J=1.5 Hz, 1H); 7.31 (broad s, 1H); 7.41 (broad s, 1H); 7.86 (s, 1H);8.23 (s, 1H); 9.37 (d, J=4 Hz, 1H); 9.45 (d, J=4 Hz, 1H); 9.6-10.00 (m,about 3H) ppm.

The2-[2-(aminooxy)-2-methylpropionyl]-1-[(3,4-dihydroxyphenyl)sulphonyl]hydrazineused as the starting material was prepared as follows:

a) 2.9 g of 3,4-diacetoxy-benzenesulphochloride were added to a mixtureof 5.15 g of hydrazine hydrate and 10 ml of water and the mixture washeated to 70° C. for 1 hour. The clear solution was cooled and thesolvent is evaporated off in a vacuum. The residue was taken up in waterand chromatographed on MCI gel CHP2OP. Elution was carried out firstwith water and subsequently with water/methanol mixtures usingincreasing amounts of methanol. The product fractions were concentratedcompletely in a vacuum and the residue was crystallized frommethanol/diethyl ether. There was obtained 3,4-dihydroxybenzenesulphonichydrazide as white crystals having a melting point of 172° C. (dec.).

b) A mixture of 204 mg of 3,4-dihydroxybenzenesulphonic hydrazide and379 mg of 2-methyl-2-(phthalimidooxy)thiopropionic acidS-(2-benzothiazolyl) ester was heated to 60° C. in 5 ml of acetonitrilefor 3 hours. After cooling, any undissolved material was filtered offunder suction. The filtrate was freed from solvent in a vacuum and theresidue was taken up in 3 ml of ethanol. The suspension was treated with100 mg of hydrazine hydrate and stirred at 20° C. for 1 hour. A clearsolution first resulted, from which a white precipitate separated out.Undissolved material was filtered off and the filtrate was evaporated ina vacuum. The crystalline residue was triturated with 10 ml of 0.1Naqueous hydrochloric acid for 10 minutes and the insoluble material wasseparated by filtration. The filtrate was adjusted to pH 7 by theaddition of 2N aqueous sodium hydroxide solution and chromatographed onMCI gel CHP2OP, with elution being carried out first with 2% aqueousacetic acid and then with water/methanol (9:1, v/v). By evaporation ofthe product fractions in a vacuum, there was obtained2-[2-(aminooxy)-2-methylpropionyl]-1-[(3,4-di-hydroxyphenyl)sulphonyl]hydrazineas white crystals of melting point 220° C. (dec.).

¹ H NMR (DMSO-d₆): δ1.10 (s, 6H); 5.89 (broad s, 2H); 6.78 (d, J=8 Hz,1H); 7.09 (dd, J=8 and 2 Hz, 1H); 7.16 (d, J=2 Hz, 1H) ppm.

EXAMPLE 11

122 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with236 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[[2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid according to the procedure described in Example 7. The crudeproduct obtained was suspended in 10 ml of water and brought intosolution by the slow addition of 0.1N sodium hydroxide solution, withcare being taken that the pH of the solution did not exceed 7. Bychromatography on MCI gel CHP 2OP using water as the elution agent aswell as water/methanol mixtures with increasing amounts of methanol andlyophilization of the concentrated product fractions, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]-imino]acetamido]-3-[[(2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt asa white powder.

¹ H NMR (DMSO-d₆): δ2.61 (s, 3H); 3.11 (d, J=18 Hz, 1H); 3.47 (d, J=18Hz, 1H); 3.93 (s, 3H); 4.35 (d, J=15 Hz, 1H); 4.56 (d, J=15 Hz, 1H);4.91 (d, J=5 Hz, 1H); 5.11 (d, J=15 Hz, 1H); 5.20 (d, J=15 Hz, 1H); 5.42(dd, J=7 Hz and 5 Hz, 1H); 6.78 (s, 1H); 6.86 (d, J=8 Hz, 1H); 7.16 (d,J=1 Hz, 1H); 7.22-7.36 (m, about 4H); 7.84 (s, 1H); 9.43 (d, J=7 Hz, 1H)ppm.

The starting material was prepared as follows:

a) 1.10 g of methyl7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate and 1.34 gof (7R)-7-amino-cephalosporanic acid were suspended in 5 ml ofacetonitrile and treated with 10 ml of a 20 percent solution of borontrifluoride in acetonitrile and stirred at 20° for 90 minutes. Thereaction mixture was treated with 40 ml of water and the pH was adjustedto 2.5 by means of 28 percent sodium hydroxide solution. After stirringat 0° for 1 hour, the precipitate was filtered off under suction anddried. There was obtained (6R,7R)-7-amino-3-[[2-(methoxycarbonyl)-[5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.62 (s, 1H); 3.57 (d, J=12 Hz, 1H); 3.77 (d, J=18Hz, 1H); 3.94 (s, 3H); 4.37 (d, J=12 Hz, 1H); 4.45 (d, J=12 Hz, 1H);4.86 (d, J=5 Hz, 1H); 5.04 (d, J=5 Hz, 1H); 7.44 (s, 1H) ppm.

IR (KBr): 1784 cm⁻¹.

b) 1.50 g of (6R,7R)-7-amino-3-[[2-(methoxycarbonyl)-[5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylicacid in 7.5 ml of acetonitrile and 7.5 ml of water were brought intosolution with 0.49 ml of triethylamine. The solution was treated with1.50 g of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl)ester and stirred at 20° for 1 hour. The reaction mixture waspartitioned between water and ethyl acetate and the aqueous phase waschromatographed on Optiup (C₁₂) (Antec AG, CH-Bennwil) with a gradientof 0% to 10% acetonitrile in water. The product fractions wereconcentrated to about 25 ml and the pH was adjusted to 2.5. Theprecipitate was filtered off under suction and dried. There was obtained(6R,7R)-7-(2-amino-4-thiazole-glyoxylamido)-3-[[[2-(methoxycarbonyl)-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a yellow powder.

¹ H NMR (DMSO-d₆): δ2.62 (s, 3H), 3.62 (d, J=18 Hz, 1H); 3.80 (d, J=18Hz, 1H); 3.94 (s, 3H); 4.40 (d, J=12 Hz, 1H); 4.50 (d, J=12 Hz, 1H);5.20 (d, J=5 Hz, 1H); 5.78 (dd, J=8 Hz and J=5 Hz, 1H); 7.41 (s, 2H);7.46 (s, 1H); 7.82 (s, 1H); 9.81 (d, J=8 Hz, 1H) ppm.

IR (KBr): 1776 cm⁻¹.

EXAMPLE 12

307 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with531 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in an analogous manner to the procedure described in Example 11 orExample 7. There was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(7-methylpyrazolo[1,5-a]pyridin-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid monosodium salt as a white powder.

¹ H NMR (DMSO-d₆): δ2.63 (s, 3H); 3.11 (d, J=18 Hz, 1H); 3.49 (d, J=18Hz, 1H); 4.21 (d, J=13 Hz, 1H); 4.49 (d, J=13 Hz, 1H); 4.94 (d, J=5 Hz,1H); 5.20 (d, J=14 Hz, 1H); 5.27 (d, J=14 Hz, 1H); 5.46 (m, 1H); 6.54(d, J=1 Hz, 1h) 6.76 (s, 1H); 6.79 (d, J=10 Hz, 1H); 6.93 (s, 1H); 7.10(d, J=1 Hz, 1H); 7.19 (dd, J=10 and 1 Hz, 1H); 8.09 (d, J=1 Hz, 1H);9.44 (broad s, 1H) ppm.

The starting material was be prepared as follows:

a) 7.20 g of methyl5-mercapto-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylate were heatedto 100° in 2N sodium hydroxide solution until almost all had dissolved.The solution was cooled, filtered and the filtrate was adjusted to pH 2.The product was filtered off under suction, washed with water andacetone and dried. There was obtained5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid of m.p.225° (dec.).

¹ H NMR (DMSO-d₆): δ2.50 (s, 3H); 6.80 (s, 1H); 8.25 (s, 1H) ppm.

MS (70 eV): 209 (M⁺).

b) 2.00 g of 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid were heated to 220° under argon for 1 hour. After cooling, thereaction mixture was taken up in 10 percent potassium hydrogen carbonatesolution. The insoluble portion was filtered off under suction and takenup in water. The solution was acidified to pH 2 and the precipitate wasfiltered off under suction. After drying, there was obtained7-methylpyrazolo[1,5-a]pyrimidine-5-thiol.

¹ H NMR (DMSO-d₆): δ2.50 (s, 3H); 6.04 (d, J=2 Hz, 1H); 6.71 (s, 1H);7.93 (d, J=2 Hz, 1H); 13.8 (s, broad, 1H) ppm.

MS (70 eV): 165 (M⁺).

c) 0.70 g of 7-methylpyrazolo[1,5-a]pyrimidine-5-thiol and 1.15 g of(7R)-7-amino-cephalosporanic acid were dissolved in 10 ml of a 20percent solution of boron trifluoride in acetonitrile and stirred atroom temperature for 1 hour. The reaction mixture was concentrated andtaken up in 10 ml of water. The solid was filtered off under suction.There was obtained(6R,7R)-7-amino-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a reddish powder.

¹ H NMR (DMSO-d₆): δ2.64 (s, 3H); 3.48 (d, J=18 Hz, 1H); 3.74 (d, J=18Hz, 1H); 3.97 (d, J=12 Hz, 1H); 4.72 (d, J=12 Hz, 1H); 4.78 (d, J=5 Hz,1H); 4.98 (d, J=5 Hz, 1H); 6.56 (d, J=2 Hz, 1H); 6.88 (s, 1H); 8.12 (d,J=2 Hz, 1H) ppm.

IR (KBr): 1799 (cm⁻¹).

d) 1.00 g of(6R,7R)-7-amino-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid was brought into solution in 5 ml of acetonitrile and 5 ml of waterwith 0.37 ml of triethylamine. The solution was treated with 1.0 g of2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl) ester andstirred at 20° for 1 hour. The reaction mixture was partitioned betweenwater and ethyl acetate and the aqueous phase was chromatographed onOptiup (C₁₂) (Antec AG, CH-Bennwil) with a gradient of 0% to 10%acetonitrile in water. The product fractions were concentrated to 10 mland adjusted to pH 2.2 with HCl. The precipitate was filtered off undersuction. There was obtained(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.

¹ H NMR (DMSO-d₆): δ2.64 (s, 3H); 3.54 (d, J=18 Hz, 1H); 3.28 (d, J=18Hz, 1H); 4.00 (d, J=12 Hz, 1H); 4.78 (d, J=12 Hz, 1H); 5.14 (d, J=5 Hz,1H); 5.72 (dd, J=8 Hz and J=5 Hz, 1H); 6.56 (d, J=2 Hz, 1H); 6.89 (s,1H); 7.43 (s, 2H); 7.80 (s, 1H); 8.12 (s, 1H); 9.79 (d, J=8 Hz, 1H) ppm.

IR (KBr): 1776 (cm⁻¹.

EXAMPLE 13

307 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with575 mg of(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in an analogous manner to the procedure described in Examples 11 or7. There was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.67 (s, 3H); 3.68 (d, J=18 Hz, 1H); 3.81 (d, J=18Hz, 1H); 4.20 (d, J=14 Hz, 1H); 4.55 (d, J=14 Hz, 1H); 5.12 (d, J=5 Hz,1H); 5.15 (d, J=13 Hz, 1H); 5.23 (d, J=13 Hz, 1H); 5.70 (dd, J=8 and 5Hz, 1H); 6.67 (s, 1H); 6.90 (d, J=9 Hz, 1H); 7.09-7.23 (m, 3H); 7.28(broad s, 2H); 8.48 (s, 1H); 9.69 (d, J=8 Hz, 1H); 10.10 (broad s, 1H)ppm.

The starting material was prepared as follows:

a) A suspension of 4.00 g of (7R)-7-aminocephalosporanic acid and 3.34 gof 5-mercapto-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylic acid in 20ml of acetonitrile was treated with 25 ml of a 20 percent solution ofboron trifluoride in acetonitrile and the mixture was stirred at 20° for1.5 hours. 150 ml of cold water were added and the mixture was stirredat 0° for 1.5 hours. The precipitate was filtered off under suction anddried. There was obtained(6R,7R)-7-amino-3-[[(3-carboxy-7-methylpyrazolo-[1,5-a]pyri-midine-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid as an almost colorless powder.

¹ H NMR (DMSO-d₆): δ2.67 (s, 3H); 3.76 (m, 2H); 4.18 (d, J=12 Hz, 1H);4.52 (d, J=12 Hz, 1H); 4.80 (d, J=5 Hz, 1H); 5.00 (d, J=5 Hz, 1H); 7.14(s, 1H); 8.47 (s, 1H) ppm. MS (70 eV) 422 (M+H)⁺.

b) 3.00 g of(6R,7R)-7-amino-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidine-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid were brought into solution in 15 ml of acetronitrile and 15 ml ofwater with 1.02 ml of triethylamine. The solution was treated with 3.15g of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl) ester andstirred for 1 hour. The reaction mixture was partitioned between waterand ethyl acetate and the aqueous phase was chromatographed on Optiup(C₁₂) (Antec AG, CH-Bennwil) with a gradient of 0% to 20% acetonitrilein water. The product fractions were concentrated to about 50 ml and thepH was adjusted to 2.5. The precipitate was filtered off under suction.After drying, there was obtained(6R,7R)-7-(2-amino-4-thiazole-glyoxylamido)-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyri-midin-5-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.

¹ H NMR (DMSO-d₆): δ2.67 (s, 3H); 3.83 (m, 2H); 4.22 (d, J=12 Hz, 1H);4.54 (d, J=12 Hz, 1H); 5.17 (d, J=5 Hz, 1H); 5.71 (dd, J=8 Hz and J=5Hz, 1H); 7.15 (s, 1H); 7.41 (s, 2H); 7.80 (s, 1H); 8.47 (s, 1H); 9.76(d, J=8 Hz, 1H) ppm.

IR (KBr): 1778 cm⁻¹.

EXAMPLE 14

613 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with1.06 g of(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(5-mthylpyrazolo]1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in an analogous manner to the procedure described in Example 11 orExample 7. There was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid monosodium salt as a white powder.

¹ H NMR (DMSO-d₆): δ2.50 (s, 3H); 3.17 (d, J=18 Hz, 1H); 3.50 (d, J=18Hz, 1H); 4.27 (d, J=14 Hz, 1H); 4.53 (d, J=14 Hz, 1H); 4.96 (d, J=5 Hz,1H); 5.09 (d, J=13 Hz, 1H); 5.15 (d, J=13 Hz, 1H); 5.46 (d, J=5 Hz, 1H);6.51 (d, J=0.2 Hz, 1H); 6.72 (d, J=8 Hz, 1H); 6.77 (s, 1H); 7.06 (d,J=0.2 Hz, 1H); 7.17 (dd, J=8 and 0.2 Hz, 1H); 7.31 (s, 1H); 8.11 (d,J=0.2 Hz, 1H); 9.48 (broad s, 1H) ppm.

The starting material was prepared as follows:

a) 110 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid were heated to reflux temperature for 2.5 hours in 500 ml of 20percent hydrochloric acid. The reaction mixture was cooled, the productwas filtered off under suction and then recrystallized fromwater/ethanol at a pH of 6. There was obtained 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol as yellow crystals of a melting point above250°.

¹ H NMR (DMSO-d₆): δ2.33 (s, 3H); 6.31 (d, J=2 Hz, 1H); 6.67 (s, 1H);8.06 (d, J=2 Hz, 1H); 13.3 (s, broad, 1H) ppm.

MS (70 eV): 165 (M⁺).

b) 1.1 g of 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol and 1.80 g of(7R)-7-aminocephalosporanic acid were stirred for 1 hour in 18 ml of a20 percent solution of boron trifluoride in acetonitrile. The reactionmixture was concentrated, the residue was taken up in 15 ml of water,and the pH was adjusted to 2.5 with 2N sodium hydroxide solution. Theprecipitated product was filtered off under suction and dried. There wasobtained(6R,7R)-7-amino-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

¹ H NMR (DMSO-d₆): δ2.50 (s, 1H); 3.54 (d, J=18 Hz, 1H); 3.77 (d, J=18Hz, 1H); 4.24 (d, J=12 Hz, 1H); 4.40 (d, J=12 Hz, 1H); 4.80 (d, J=5 Hz,1H); 5.03 (d, J=5 Hz, 1H); 6.57 (d, J=2 Hz, 1H); 6.98 (s, 1H); 8.15 (d,J=2 Hz, 1H) ppm.

IR (KBr): 1794.

c) 2.30 g of(6R,7R)-7-amino-3-[[(5-methylpyrazolo-[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicylco[4.2.0]oct-2-ene-2-carboxylicacid were brought into solution in 12.5 ml of water and 12.5 ml ofacetonitrile with 0.80 ml of triethylamine. The solution was treatedwith 2.30 g of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl)ester and stirred at 20° for 45 minutes. The reaction mixture waspartitioned between water and ethyl acetate and the aqueous phase waschromatographed on Optiup (C₁₂) (Antec AG, Bennwil) with a gradient of0% to 10% acetonitrile in water. The product fractions were concentratedand the pH was adjusted to 2.2. The precipitate was filtered off undersuction and dried. There was obtained(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbonxylicacid.

¹ H NMR (DMSO-d₆): δ2.50 (s, 3H); 3.62 (d, J=18 Hz, 1H); 3.81 (d, J=18Hz, 1H); 4.31 (d, J=12 Hz, 1H); 4.45 (d, J=12 Hz, 1H); 5.22 (d, J=5 Hz,1H); 5.78 (dd, J=8 Hz and J=5 Hz, 1H); 5.67 (d, J=2 Hz, 1H); 6.99 (s,1H); 7.42 (s, 2H); 7.82 (s, 1H); 8.16 (d, J=2 Hz, 1H); 9.84 (d, J=8 Hz,1H) ppm.

IR (KBr): 1776 cm⁻¹.

EXAMPLE 15

120 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with220 mg of(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in an analogous manner to the procedure described in Example 11 orExample 7. The crude product was suspended in about 4 ml of water andbrough into solution by the slow addition of 1N sodium hydroxidesolution, with care being taken that the pH of the solution did notexceed 7. By chromatography on MCI gel CHP 20P using 0.005M sodiumphosphate buffer and increasing amounts of acetonitrile as the eluent,there was obtained purified product which was isolated by concentrationand acidification of the pure fractions with 1N HCl. By dissolving thismaterial in water with the addition of 1 equivalent of sodium hydroxidesolution and subsequent lyophilization, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-5-thiazolo[1,5-a]pyrimidin-7-yl]-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid monosodium salt as a white powder.

¹ H NMR (DMSO-d₆): δ inter alia 2.56 (s, 3H), 3.09 (d, J=18 Hz, 1H);3.48 (d, J=18 Hz, 1H); 4.29 (d,J=14 Hz, 1H); 4.55 (d,J=14 Hz, 1H); 4.61(s, 2H); 4.92 (d,J=5 Hz, 1H); 5.14 (d,J=13 Hz, 1H); 5.22 (d,J=13 Hz,1H); 5.44 (m, 1H); 6.78 (s, 1H); 6.66 (d,J=8 Hz, 1H); 7.1-7.4 (m, 4H);7.60 (s, 1H); 9.42 (d,J=8 Hz, 1H) ppm.

The starting material was be prepared as follows:

a) 2.24 g of methyl7-mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidine-2-carboxylate weresuspended in 350 ml of tetrahydrofuran and treated at 2° within 15minutes with 40 ml of a 1M diisobutylaluminium hydride/hexane solution.The reaction mixture was stirred at 2° for 10 minutes and subsequentlytreated with ice. The reaction mixture was concentrated extensively, theresidue was taken up in 30 ml of water, and the solution was acidifiedto pH 1.2 with concentrated hydrochloric acid. The solid was collectedby filtration and dried in a high vacuum. There was obtained7-mercapto-5-methyl-s-tria-zolo[1,5-a]pyrimidine-2-methanol of meltingpoint 233° (dec.).

¹ H NMR (DMSO-d₆): δ2.33 (s, 3H); 4.59 (s, 2H); 6.87 (s, 1H) ppm.

b) 0.400 g of7-mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidine-2-methanol and 0.520 gof (7R)-7-aminocephalosporanic acid were dissolved in 5.0 ml of a 20percent solution of boron trifluoride in acetonitrile and the solutionwas stirred at 20° for 30 minutes. The reaction mixture was diluted with10 ml of water and adjusted to pH 3.0 with 2N sodium hydroxide solution.The resulting precipitate was filtered off and dried. There was obtained(6R,7R)-7-amino-3-[[[(2-hydroxymethyl)-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicylco-[4.2.0]oct-2-ene-2-carboxylicacid as a beige powder.

¹ H NMR (DMSO-d₆): δ2.57 (s, 3H); 3.54 (d,J=18 Hz, 1H); 3.75 (d,J=18 Hz,1H); 4.31 (d,J=12 Hz, 1H); 4.44 (d,J=12 Hz, 1H); 4.62 (s, 2H); 4.81(d,J=5 Hz, 1H); 5.02 (d,J=5 Hz, 1H); 7.25 (s, 1H).

c) 0.70 g of(6R,7R)-7-amino-3-[[[(2-hydroxy-methyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid were suspended in 10 ml of N,N-dimethylformamide and 10 ml ofmethylene chloride and brought into solution by the addition of 1.62 mlof N,O-bis-(trimethylsilyl)-acetamide. The mixture was cooled to 0°,treated with 0.95 g of 2-amino-4-thiazolethio-glyoxylic acidS-(2-benzothiazolyl) ester and stirred at this temperature for 1.5hours. The reaction mixture was partitioned between ethyl acetate andsaturated sodium hydrogen carbonate solution. The aqueous phase waschromatographed on Opti-Up C₁₂ with water to 5% acetonitrile in water.Uniform fractions were concentrated and adjusted to pH 2.5 with 1Nhydrochloric acid. The precipitated product was filtered off and driedin a high vacuum. There was obtained(6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[2-(hydroxymethyl)-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a yellow powder.

¹ H NMR (DMSO-d₆): δ2.58 (s, 3H); 3.60 (δ, J=18 Hz, 1H); 3.82 (d, J=18Hz, 1H); 4.37 (δ, J=12 Hz, 1H); 4.50 (d, J=12 Hz, 1H); 4.62 (s, 2H);5.22 (d, J=5 Hz, 1H); 5.77 (dd, J=5 and 8 Hz, 1H); 7.26 (s, 1H); 7.44(s, broad 2H); 7.84 (s, 1H); 9.83 (d, J=8 Hz, 1H) ppm.

EXAMPLE 16

161 mg of 2-amino-4-thiazoleglyoxylic acid(Z)-O-[2-[(3,4-dihydroxyphenyl)sulphonamido]ethyl] oxime were reactedwith 206 mg of (6R,7R)-7-amino-3-[[2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid hydrochloride according to the procedure described in Example 1.The working-up procedure described in Example 1 yielded an aqueousphase, which was adjusted to pH 9 and applied to a MCI gel column(CHP2OP) conditioned with 1% aqueous acetic acid. Elution was carriedout first with 1% aqueous acetic acid, then with water, and finally withwater/acetonitrile mixtures using increasing amounts of acetonitrile.The product was eluted with a 4:1 (v/v) water/acetonitrile mixture. Bylyophilization of the product fractions, which were concentrated in avacuum, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[2-[(3,4-dihydroxyphenyl)sulphonamido]ethoxy]imino]-acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.61 (s, 3H); 2.98 (dt, J=7 and 7 Hz, 1H); 3.53 (d,J=17 Hz, 1H); 3.78 (d, J=17 Hz, 1H); 3.98 (t, J=7 Hz, 1H); 4.37 (d, J=13Hz, 1H); 4.50 (d, J=13 Hz, 1H); 5.18 (d, J=5 Hz, 1H); 5.81 (dd, J=8 and5 Hz, 1H); 6.74 (s, 1H); 6.86 (d, J=8 Hz, 1H); 7.09 (dd, J=8 and 2 Hz,1H); 7.15 (d, J=2 Hz, 1H); 7.28 (broad s, 2H); 7.34 (t, J=7 Hz, 1H);7.39 (s, 1H); 7.88 (s, 1H); 8.17 (s, 1H); 9.56 (d, J=8 Hz, 1H); 9.67(broad s, 1H); 9.91 (broad s, 1H) ppm.

The 2-amino-4-thiazoleglyoxylic acid(Z)-O-[2-[(3,4-dihydroxyphenyl)sulphonamido]ethyl] oxime used as thestarting material was prepared as follows:

a) A solution of 10 g of 2-amino-4-thiazoleglyoxylic acid ethyl ester(Z)-O-(2-bromoethyl) oxime in 100 ml of methylene chloride was treatedin succession with 3.14 ml of triethylamine and a solution of 8.8 g oftrityl chloride in 50 ml of methylene chloride. The reaction solutionwas stirred at 20° C. for 18 hours, washed with water, and then driedover magnesium sulphate. The solvent was removed in a vacuum, upon whichcrude 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester(Z)-O-(2-bromoethyl) oxime was obtained as an oil.

b) A solution of 17.5 g of 2-(tritylamino)-4-thiazoleglyoxylic acidethyl ester (Z)-O-(2-bromoethyl) oxime and 5 g of sodium azide in 200 mlof N,N-dimethylformamide was stirred at 50° C. for 15 hours. Thereaction solution was cooled to 20° C. and partitioned between ethylacetate and water. The organic phase was dried over sodium sulphate andthe solvent was removed in a vacuum. Crude2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester(Z)-O-(2-azido-ethyl) oxime was obtained as an oil.

c) 16.4 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester(Z)-O-(2-azidoethyl) oxime were hydrogenated for 3.5 hours under normalpressure in 300 ml of methanol in the presence of 2.5 g ofpalladium/carbon (5%). The catalyst was filtered off and the solvent wasremoved in a vacuum. The residue was crystallized from carbontetrachloride/petroleum ether (low-boiling). There was obtained2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester(Z)-O-(2-aminoethyl) oxime as white crystals having a melting point of126°-144° C.

d) 1.17 g of 3,4-diacetoxy-benzenesulphonyl chloride were added to asolution of 6.0 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethylester (Z)-O-(2-aminoethyl) oxime and 0.49 g of 4-dimethylamino-pyridinein 50 ml of N,N-dimethylformamide. The reaction solution was stirred at20° C. for 3 hours, 10 ml of 2N sodium hydroxide solution were thenadded, and the solution was stirred at 20° C. for an additional hour.Then, 20 ml of water were added and the pH of the reaction mixture waslowered to 3 by the addition of 3N hydrochloric acid. The resultingprecipitate was filtered off under suction, washed with a small amountof water and then heated to 50° C. for 40 minutes in 60 ml of 80%aqueous acetic acid. The mixture was cooled to 20° C. and evaporatedcompletely in a vacuum. The residue was dissolved in 30 ml of methanoland treated in an ice bath with a total of 180 ml of diethyl ether. Theprecipitate was filtered off under suction, suspended in a small amountof water and brought into solution by the dropwise addition of 2N sodiumhydroxide solution. The solution of pH 7.5 was applied to a MCI gelcolumn (CHP2OP) conditioned with 1% aqueous acetic acid andchromatographed according to the procedure described in the firstparagraph of this Example. The product was eluted with a 9:1 (v/v)water/acetonitrile mixture. The pure fractions were concentratedcompletely in a vacuum and the solid residue was crystallized frommethanol/diethyl ether. There was obtained 2-amino-4-thiazoleglyoxylicacid (Z)-O-[2-[(3,4-dihydroxyphenyl)sulphonamido]ethyl] oxime as whitecrystals of melting point 92°-94° C. (decomposition).

¹ H NMR (DMSO-d₆): δ2.94 (dd, J=7 and 5 Hz); 4.01 (t, J=7 Hz, 1H); 6.83(s, 1H); 6.87 (d, J=9 Hz, 1H); 7.09 (dd, J=9 and 1.5 Hz, 1H); 7.18 (d,J=1.5 Hz, H); 7.25 (broad s, 2H); 7.44 (t, J=5 Hz, 1H); 9.89 (broad s,1H) ppm.

EXAMPLE 17

A mixture of 146 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-iodoethoxy)imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, 75 mg of 2,2-diphenyl-1,3-benzodioxol-5-sulphinic acid lithiumsalt and 24 mg of sodium hydrogen carbonate in 0.5 ml ofN,N-dimethylformamide was stirred at 20° C. for 24 hours. The reactionmixture was treated with 5 ml of water and the pH of the mixture waslowered to 3 by the addition of 3N hydrochloric acid. The resultingprecipitate was filtered off under suction, washed with a small amountof water and then dissolved in 4 ml of water with the addition of smallamount of 2N sodium hydroxide solution. This solution, of pH 7.5, wasapplied to a MCI gel column (CHP2OP) conditioned with 1 % aqueous aceticacid and chromatographed according to the procedure described in Example16. The fraction eluted with a 1:1 (v/v) water/acetonitrile mixture wasconcentrated in a vacuum and lyophilized. The lyophilizate was dissolvedin 90% aqueous trifluoroacetic acid and the solution was stirred at 20°C. for 20 minutes. The solvents were removed in a vacuum and the residuewas partitioned between ethyl acetate and 2% sodium hydrogen carbonatesolution. The aqueous phase was chromatographed according to theprocedure described in Example 16. After concentration andlyophilization of the pure fractions, there was obtained(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[2-[(3,4-dihydroxyphenyl)-sulphonyl]ethoxy]imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white powder.

¹ H NMR (DMSO-d₆): δ2.58 (s, 3H); 3.53 (m, 3H); 3.78 (d, J=18 Hz, 1H);4.21 (m, 2H); 4.33 (d, J=13 Hz, 1H); 4.50 (d, J=13 Hz, 1H); 4.62 (s,2H); 5.17 (d, J=5 Hz, 1H); 5.55 (broad s, 1H); 5.78 (dd, J=8 and 5 Hz,1H); 6.78 (s, 1H); 6.94 (d, J=8 Hz, 1H); 7.18-7.28 (m, 6H); 9.50 (d, J=8Hz, 1H); 9.85 (broad s, 1H); 10.20 (broad s, 1H) ppm.

The(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-iodoethoxy)imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid used as the starting material was prepared as follows:

a) A solution of 3.41 g of 2-amino-4-thiazoleglyoxylic acid(Z)-O-(2-iodoethyl) oxime in 50 ml of N,N-dimethylformamide was cooledto 0° C. and treated in succession with 1.36 g of1-hydroxy-benzotriazole and 2.04 g of N,N'-dicyclohexylcarbodiimide. Thereaction mixture was stirred at 0° C. for 2 hours, upon which aprecipitate formed, and it was then treated with a solution, pre-cooledto 0° C., of 4.08 g of(6R,7R)-7-amino-3-[[[(2-hydroxymethyl)-5-methyl-s-tria-zolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 1.1 g of triethylamine in 40 ml of N,N-dimethylformamide. Themixture was stirred at 0° C. for 3 hours. The resulting precipitate wasfiltered off under suction and the filtrate was poured into 400 ml ofwater. The pH of the solution was lowered to 3.0 by the addition of 3Nhydrochloric acid. After stirring in an ice bath for 10 minutes, theprecipitate was filtered off under suction and washed with water. Theresidue on the filter was suspended in a small amount of water anddissolved by the slow addition of about 2 ml of 2N sodium hydroxidesolution. This solution, of pH 7.5, was applied to a MCI gel column(CHP20P) conditioned with 1% aqueous acetic acid and chromatographedaccording to the procedure described in Example 16. The product waseluted with a 4:1 (v/v) water/acetonitrile mixture. The productfractions were concentrated in a vacuum and the product was precipitatedby acidifying the solution to pH 2.8 with 3N hydrochloric acid.(6R,7R)-7-[(Z)-2-(2-Amino-4-thiazolyl)-2-[(2-iodoethoxy)imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid was isolated as a beige powder.

¹ H NMR (DMSO-d₆): δ2.58 (s, 3H); 3.35 (t, J=7 Hz, 2H); 3.58 (d, J=14Hz, 1H); 3.76 (d, J=14 Hz, 1H); 4.27 (t, J=7 Hz, 2H); 4.35 (d, J=11 Hz,1H); 4.44 (d, J=11 Hz, 1H); 4.62 (s, 2H); 5.19 (d, J=4 Hz, 1H); 5.54(broad s, 1H); 5.81 (dd, J=8 and 4 Hz, 1H); 6.79 (s, 1H); 7.27 (broad s,3H); 9.64 (d, J=8 Hz, 1H) ppm.

The 2,2-diphenyl-1,3-benzodioxol-5-sulphinic acid lithium salt used asthe starting material was prepared as follows:

a) 18.75 g of N-bromosuccinimide are added to a solution of 27.4 g of2,2-diphenyl-1,3-benzodioxol in 80 ml of chloroform and the mixture wasboiled at reflux for 20 hours. The reaction mixture was cooled and theseparated succinimide was filtered off. The filtrate was washed withwater, dried over sodium sulphate and the solvent was removed in avacuum. By crystallization of the residue from ethanol, there wasobtained 5-bromo-2,2-diphenyl-1,3-benzodioxol as white crystals ofmelting point 88°-89° C.

b) A solution of 14.13 g of 5-bromo-2,2-diphenyl-1,3-benzodioxol in 60ml of diethyl ether was added dropwise at -50° C. within 5 minutes to amixture of 24 ml of 1.7M butyllithium/hexane solution and 40 ml ofdiethyl ether. The reaction solution was stirred for 40 minutes, duringwhich period the temperature was allowed to rise to -15° C. The solutionwas again cooled to -50° C. and then sulphur dioxide was conductedthrough the solution for 15 minutes, upon which a white precipitateformed. The reaction mixture was warmed to 20° C. and excess sulphurdioxide was driven off by means of a weak stream of argon. The mixturewas suction filtered and the material on the suction filter was washedwith diethyl ether and dried in a vacuum. There was obtained2,2-diphenyl-1,3-benzodioxol-5-sulphic acid lithium salt as a white,amorphous material of melting point 120°-130° C. (decomposition).

¹ H NMR (DMSO-d₆): δ6,92 (d,J=8 Hz, 1H); 6,97(dd, J=8 und 1 Hz, 1H);7,08 (d,J=1 Hz, 1H); 7,35-7,6 (m, 15H) ppm

EXAMPLE A Manufacture of Dry Ampoules for Intramuscular Administration

A lyophilizate of 1 g of the sodium salt of(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)-sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is prepared in the usual manner and filled into an ampoule. Priorto the administration, the lyophilizate is treated with 2.5 ml of a 2%aqueous lidocaine hydrochloride solution.

The same procedure is also used for(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-5-thiazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid monosodium salt.

I claim:
 1. A compound of the formula ##STR18## wherein R is a phenylgroup or a phenyl group which is mono-, di-, or trisubstituted withhalogen, hydroxy, nitro, amino, cyano, trifluoromethyl, lower alkyl orlower alkoxy, a 5-membered aromatic heterocyclic group which has as thehetero (non-carbon) ring member(s) an oxygen or sulphur atom or an iminoor lower alkylimino group and optionally one or two nitrogen atoms, or a6-membered aromatic heterocyclic group, which has one to three nitrogenatoms as the hetero ring member(s); A is lower alkylene or C₃₋₇-cycloalkylene which is optionally substituted with carboxy, carbamoyl,lower alkylcarbamoyl or di(loweralkyl)carbamoyl; Q is lower alkylene orC₃₋₇ -cycloalkylene which is optionally substituted with carboxy,carbamoyl, lower alkylcarbamoyl or di(lower alkyl)carbamoyl; or thegroup --NR² --, or --NR² NR³ --; R² and R³ are independently hydrogen orlower alkyl; p and m are zero or 1; n is zero, 1 or 2; R⁴ is hydrogen,lower alkanoyl or tri(lower alkyl)silyl; two R⁴ groups togetherrepresent diphenylmethylene; R⁵ is hydrogen, lower alkyl, hydroxy, loweralkoxy, halogen, nitro, --OCOR⁷, --OCOOR⁷¹, --N(R⁷)₂, --NHCOR⁷,--NHCOOR⁷¹, --COR⁷, --SR⁷, --SOR⁷, SO₂ R⁷, --SO₃ H, --COOR⁷ or--CON(R⁷)₂, R⁶ is hydrogen, lower alkyl or halogen, R⁷ is hydrogen orlower alkyl and R⁷¹ is lower alkyl, and the two --OR⁴ groups areattached to the phenyl ring via adjacent carbon atoms.
 2. A compoundaccording to claim 1, 2-amino-4-thiazoleglyoxylicacid(Z)-O-[[(3,4-dihydroxyphenyl)]-sulphonyl]methyl]oxime.